ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1127T>G (p.Phe376Cys) (rs80358410)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203669 SCV000071755 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-07 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 376 of the BRCA2 protein (p.Phe376Cys). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51068). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 2019-10-22 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 RCV000043742 SCV000210263 likely benign not specified 2016-08-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000112882 SCV000488358 uncertain significance Breast-ovarian cancer, familial 2 2016-03-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130007 SCV000683402 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-22 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 performed for this variant. This variant has been reported in a multifactorial analysis as likely benign (posterior probability of 0.009) influenced by family history (PMID: 31131967). 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112882 SCV000145818 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.