Submissions for variant NM_007294.4(BRCA1):c.4625C>G (p.Ser1542Cys)

gnomAD frequency: 0.00004  dbSNP: rs41293457

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048609	SCV000076622	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129407	SCV000184176	likely benign	Hereditary cancer-predisposing syndrome	2021-10-28	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703953	SCV000296482	uncertain significance	not provided	2020-11-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000112366	SCV000488159	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001703953	SCV000520748	likely benign	not provided	2018-05-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10550055, 23704879, 11240689, 11106241, 22476429, 21338495, 10815905, 11156530, 16721040, 10918303, 26898890, 11336395, 25348012, 28781887, 30765603)
Color Diagnostics, LLC DBA Color Health	RCV000129407	SCV000911163	likely benign	Hereditary cancer-predisposing syndrome	2016-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703953	SCV001473553	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing	The BRCA1 c.4625C>G; p.Ser1542Cys variant (rs41293457) is reported in the literature in individuals with breast cancer (Lu 2012, Shih 2000), and is reported in the ClinVar database (Variation ID: 55242). This variant is found in the general population with an overall allele frequency of 0.004% (9/251360 alleles) in the Genome Aggregation Database. The serine at codon 1542 is moderately conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. S1542 is phosphorylated by ATM and may be involved in response to DNA double-strand breaks (Cortez 1999). However, functional characterization of the variant suggests this variant is likely not pathogenic (Woods 2016). Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Cortez D et al. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science. 1999 Nov 5;286(5442):1162-6. Lu W et al. Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer. 2012 Sep;11(3):381-5. Shih HA et al. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clin Cancer Res. 2000 Nov;6(11):4259-64. Woods NT et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2016;1. pii: 16001.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778692	SCV002015174	uncertain significance	not specified	2021-10-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4625C>G (p.Ser1542Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251472 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00011 vs 0.001), allowing no conclusion about variant significance. c.4625C>G has been reported in the literature in individuals affected with breast and ovarian cancers (Akilzhanova_2013, Arver_2001, Koul_2000, Lu_2012, Mucaki_2016, Shih_2000, Tanner_2000). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies showed the variant to have proficient transcriptional activation (Woods_2016, Fernandes_2019) while another showed the variant to deregulate BRCA1-mediated double stranded break repair via ATM phosphorylation (Tram_2013). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001778692	SCV002072107	uncertain significance	not specified	2017-08-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001778692	SCV004242810	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112366	SCV000145132	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112366	SCV004243979	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-02	no assertion criteria provided	clinical testing