Submissions for variant NM_000059.4(BRCA2):c.2491G>A (p.Val831Ile)

gnomAD frequency: 0.00001  dbSNP: rs397507287

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204111	SCV000260892	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 831 of the BRCA2 protein (p.Val831Ile). This variant is present in population databases (rs397507287, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 11802209, 21952622, 35264596). ClinVar contains an entry for this variant (Variation ID: 37788). 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.
Ambry Genetics	RCV000221646	SCV000276726	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	The p.V831I variant (also known as c.2491G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2491. The valine at codon 831 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in 1/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80). This alteration was also detected in a cohort of 1864 men with prostate cancer between ages 36 and 88 (Kote-Jarai Z et al. Br. J. Cancer, 2011 Oct;105:1230-4). Additionally, this alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is poorly 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.
Counsyl	RCV000031369	SCV000488241	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031369	SCV001139032	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269089	SCV001448328	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2491G>A (p.Val831Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 242542 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2491G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer, prostate cancer and colon cancer (Meindl_2002, Kote-Jarai_2011, Deihimi_2017). These reports do 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. 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.
GeneDx	RCV001553524	SCV001774409	uncertain significance	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, and prostate cancer (Meindl 2002, Kote-Jarai 2011, Yoon 2021); Also known as 2719G>A; This variant is associated with the following publications: (PMID: 24755471, 24265153, 21952622, 11802209, 28591715, 33526602)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000204111	SCV002819199	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-27	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000221646	SCV003848364	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001269089	SCV004027410	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031369	SCV004834181	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 831 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 an individual affected with prostate cancer (PMID: 21952622), an individual with a personal or family history of breast cancer (PMID: 11802209), and three unaffected individuals (PMID: 33471991). This variant has been identified in 2/273536 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.
Sharing Clinical Reports Project (SCRP)	RCV000031369	SCV000053974	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-08-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031369	SCV000146057	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1999-12-30	no assertion criteria provided	clinical testing