13-32337870-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000059.4(BRCA2):āc.3515C>Gā(p.Ser1172Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1172L) has been classified as Benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3515C>G | p.Ser1172Trp | missense_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3515C>G | p.Ser1172Trp | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461764Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10AN XY: 727168
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces serine with tryptophan at codon 1172 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer and in two individuals with a personal or family history of breast cancer (PMID: 25896959, 25682074, 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA2_003877). This variant has not been identified 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 26, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 16, 2015 | - - |
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2023 | 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; Also known as 3743C>G; This variant is associated with the following publications: (PMID: 25896959, 32772980, 24817641, 29884841, 32377563, 31131967, 25682074, 33471991, 35263119, 31853058) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BRCA2: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 02, 2023 | In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 32772980 (2020), and 25896959 (2015)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 01, 2023 | The p.S1172W variant (also known as c.3515C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3515. The serine at codon 1172 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been detected in multiple breast cancer cohorts (D'Argenio V et al. Clin. Chim. Acta, 2015 Jun;446:221-5; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Nguyen-Dumont T et al. Genet Res (Camb), 2020 08;102:e6; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 14, 2022 | This missense variant replaces serine with tryptophan at codon 1172 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer and in two individuals with a personal or family history of breast cancer (PMID: 25896959, 25682074, 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA2_003877). This variant has not been identified 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | Variant summary: BRCA2 c.3515C>G (p.Ser1172Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3515C>G, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Wong-Brown_2015, D'Argenio_2015, Delahunty_2022, Nguyen-Dumont_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25682074, 25896959, 35263119, 32772980). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified at VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 18, 2023 | This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 1172 of the BRCA2 protein (p.Ser1172Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 25896959, 32772980, 35263119). ClinVar contains an entry for this variant (Variation ID: 51480). 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 not expected to disrupt BRCA2 protein function. 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. - |
BRCA2-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant classified as Uncertain significance and reported on 05-14-2019 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at