Submissions for variant NM_000059.4(BRCA2):c.7783G>T (p.Ala2595Ser)

dbSNP: rs80359007

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509610	SCV000608229	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-23	criteria provided, single submitter	clinical testing	The p.A2595S variant (also known as c.7783G>T), located in coding exon 15 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7783. The alanine at codon 2595 is replaced by serine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a personal and/or family history of HBOC-related cancer (Bisgin A et al. Breast, 2022 Oct;65:15-22; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000509610	SCV000683903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2595 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 observed in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 35753294). This variant has been identified in 1/246168 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985593	SCV001133916	uncertain significance	not provided	2019-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299396	SCV001488482	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2595 of the BRCA2 protein (p.Ala2595Ser). This variant is present in population databases (rs80359007, gnomAD 0.0009%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52408). 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 with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468999	SCV002766575	uncertain significance	not specified	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7783G>T (p.Ala2595Ser) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7783G>T has been reported in the literature in an individual affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Bisgin_2022). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000113817	SCV004845561	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2595 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 observed in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 35753294). This variant has been identified in 1/246168 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.
Baylor Genetics	RCV004566839	SCV005058343	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113817	SCV000147180	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113817	SCV000297554	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-08-29	no assertion criteria provided	clinical testing