ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.1846G>C (p.Asp616His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.1846G>C (p.Asp616His)
Variation ID: 185069 Accession: VCV000185069.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23630308 (GRCh38) [ NCBI UCSC ] 16: 23641629 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 29, 2017 May 1, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024675.4:c.1846G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Asp616His missense NC_000016.10:g.23630308C>G NC_000016.9:g.23641629C>G NG_007406.1:g.16050G>C LRG_308:g.16050G>C LRG_308t1:c.1846G>C LRG_308p1:p.Asp616His - Protein change
- D616H
- Other names
- -
- Canonical SPDI
- NC_000016.10:23630307:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
PALB2 | - | - |
GRCh38 GRCh37 |
5837 | 5876 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2023 | RCV000164427.13 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000483250.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000635889.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 25, 2020 | RCV001269117.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 26, 2024 | RCV003989339.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 20, 2021 | RCV002492657.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Uncertain significance
(Nov 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001448360.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Comment:
Variant summary: PALB2 c.1846G>C (p.Asp616His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PALB2 c.1846G>C (p.Asp616His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1846G>C has been reported in the literature in one individual affected with breast cancer (Hartley_2014) and individuals affected with LS-associated cancer and/or colorectal polyps (Yurgelun_2015, Staninova-Stojovska_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Wiltshire_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Nov 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568030.5
First in ClinVar: Apr 29, 2017 Last updated: Dec 03, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch-associated cancers and/or colon polyps and also in a patient with unilateral breast cancer; however, the variant did not segregate with breast cancer in this family (Hartley et al., 2014; Yurgelun et al., 2015; Staninova-Stojovska et al., 2019); Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wildtype (Wiltshire et al., 2020); This variant is associated with the following publications: (PMID: 25225577, 25980754, 22941656, 31942411, 31636395) (less)
|
|
Uncertain significance
(Oct 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002775794.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Sep 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202080.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222276.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMIDs: 31942411 (2019), 28944238 (2017)) and in an individual with … (more)
In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMIDs: 31942411 (2019), 28944238 (2017)) and in an individual with a family history of breast and/or ovarian cancer (PMID: 25225577 (2014)). Additionally, a functional study suggests that the variant is not damaging to PALB2 protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.0000071 (2/282802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Uncertain significance
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000757315.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 616 of the PALB2 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 616 of the PALB2 protein (p.Asp616His). This variant is present in population databases (rs786201907, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25225577). ClinVar contains an entry for this variant (Variation ID: 185069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31636395, 34946951). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Dec 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000690812.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with histidine at codon 616 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces aspartic acid with histidine at codon 616 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies with the variant demonstrated no defect in a homology-directed repair assay (PMID: 31636395). This variant has been observed in two individuals with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 31942411) and in two individuals affected with breast cancer (PMID: 25225577, 33980423). This variant has been identified in 2/282802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 5
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806909.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Uncertain significance
(Jan 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215066.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.D616H variant (also known as c.1846G>C), located in coding exon 5 of the PALB2 gene, results from a G to C substitution at nucleotide … (more)
The p.D616H variant (also known as c.1846G>C), located in coding exon 5 of the PALB2 gene, results from a G to C substitution at nucleotide position 1846. The aspartic acid at codon 616 is replaced by histidine, an amino acid with similar properties. This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). The p.D616H alteration was reported in a French Canadian woman diagnosed with breast cancer at age 25 and with a maternal and paternal family history of breast cancer (Hartley T et al. Hered Cancer Clin Pract 2014;12(1):19). This alteration has also been reported in 1/107 Macedonian individuals with a clinical history of hereditary polyposis who underwent multi-gene panel testing (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16) and in a Caucasian patient with early-onset colorectal cancer from a cohort of 1231 colorectal cancer cases (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(May 13, 2019)
|
no assertion criteria provided
Method: curation
|
not provided
Affected status: yes
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193160.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Structural Insight into the Mechanism of PALB2 Interaction with MRG15. | Redington J | Genes | 2021 | PMID: 34946951 |
Clinical Contribution of Next-Generation Sequencing Multigene Panel Testing for BRCA Negative High-Risk Patients With Breast Cancer. | Ece Solmaz A | Clinical breast cancer | 2021 | PMID: 33980423 |
Functional characterization of 84 PALB2 variants of uncertain significance. | Wiltshire T | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31636395 |
Molecular Basis of Inherited Colorectal Carcinomas in the Macedonian Population: An Update. | Staninova-Stojovska M | Balkan journal of medical genetics : BJMG | 2019 | PMID: 31942411 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. | Hartley T | Hereditary cancer in clinical practice | 2014 | PMID: 25225577 |
Text-mined citations for rs786201907 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.