Submissions for variant NM_000059.4(BRCA2):c.1127T>G (p.Phe376Cys)

dbSNP: rs80358410

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203669	SCV000071755	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 376 of the BRCA2 protein (p.Phe376Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51068). 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	RCV000130007	SCV000184832	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.F376C variant (also known as c.1127T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1127. The phenylalanine at codon 376 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
GeneDx	RCV001719792	SCV000210263	likely benign	not provided	2018-05-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10923033)
Counsyl	RCV000112882	SCV000488358	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130007	SCV000683402	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 376 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 1 individual affected with breast cancer, ovarian cancer, or melanoma (PMID: 34572941). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 controls, showing inconclusive association with disease (OR=2.653, 95%CI: 0.276 to 25.502; p-value=0.628) (PMID:33471991; Leiden Open Variation Database DB-ID BRCA2_003890). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043742	SCV000918925	uncertain significance	not specified	2018-06-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1127T>G (p.Phe376Cys) 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. Several computational tools predict a significant impact on normal splicing: Two out of five predict the variant creates a 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 120780 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1127T>G has been reported in individuals affected with Hereditary Breast and Ovarian Cancer (NHGRI BIC database). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified it as VUS and one lab classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130007	SCV003849853	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).
Myriad Genetics, Inc.	RCV000112882	SCV004020239	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
All of Us Research Program, National Institutes of Health	RCV000112882	SCV004846868	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 376 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 1 individual affected with breast cancer, ovarian cancer, or melanoma (PMID: 34572941). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 controls, showing inconclusive association with disease (OR=2.653, 95%CI: 0.276 to 25.502; p-value=0.628) (PMID:33471991; Leiden Open Variation Database DB-ID BRCA2_003890). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000112882	SCV005402400	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-25	criteria provided, single submitter	clinical testing	The BRCA2 c.1127T>G (p.Phe376Cys) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112882	SCV000145818	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000112882	SCV004228342	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)