Submissions for variant NM_000059.4(BRCA2):c.3575T>G (p.Phe1192Cys)

gnomAD frequency: 0.00003  dbSNP: rs80358606

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077308	SCV001161580	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00128 (Latino), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085848	SCV000072239	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130786	SCV000185679	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000755858	SCV000210593	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22810696, 18284688, 28591715)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755858	SCV000296713	benign	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000077308	SCV000489626	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254642	SCV000694706	benign	not specified	2022-09-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3575T>G (p.Phe1192Cys) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251062 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin.c.3575T>G has been reported in the literature in individuals affected with HBOC, colorectal cancer and gastroesophageal adenocarcinoma (Lee_2008; Keihimi_2017, Kato_2018). 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. Eight clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters to include the expert panel classified the variant as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755858	SCV000883474	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The BRCA2 c.3575T>G; p.Phe1192Cys variant (rs80358606) is reported in the ClinVar database as uncertain or likely benign (Variation ID: 51490), and observed in general population databases with an allele frequency of 0.13 percent (45/34404 alleles) in Latinos in the Genome Aggregation Database. The phenylalanine at codon 1192 is weakly conserved across species and computational algorithms (Align GVGD, SIFT, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, with the limited information regarding p.Phe1192Cys, its clinical significance is uncertain at this time. REFERENCES Link to ClinVar database for p.Phe1192Cys: https://www.ncbi.nlm.nih.gov/clinvar/variation/51490/
Color Diagnostics, LLC DBA Color Health	RCV000130786	SCV000903289	likely benign	Hereditary cancer-predisposing syndrome	2017-04-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130786	SCV002533809	likely benign	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000077308	SCV000109105	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077308	SCV000146261	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing