ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4625C>G (p.Ser1542Cys) (rs41293457)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048609 SCV000076622 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1542 of the BRCA1 protein (p.Ser1542Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs41293457, ExAC 0.01%). This variant has been observed in individuals with breast cancer and ovarian cancer (PMID: 22476429, 11106241, 11240689, 29755871), as well as in unaffected control individuals (PMID: 29755871). This variant is also known as c.4744C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55242). This variant has been reported not to substantially affect BRCA1 protein function (PMID: 28781887, 30765603). 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 RCV000129407 SCV000184176 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-14 criteria provided, single submitter clinical testing The p.S1542C variant (also known as c.4625C>G), located in coding exon 13 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4625. The serine at codon 1542 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported individuals with ovarian cancer (Tanner MM et al. Clin Cancer Res. 2000 May;6(5):1833-9; Koul A et al. Int. J. Gynecol. Cancer, 2000 Jul;10:289-295) as well as in an individual with bilateral breast cancer and colorectal cancer (Shih HA et al. Clin. Cancer Res., 2000 Nov;6:4259-64). This amino acid position is not well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112366 SCV000296482 uncertain significance Breast-ovarian cancer, familial 1 2016-05-27 criteria provided, single submitter clinical testing
Counsyl RCV000112366 SCV000488159 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000418148 SCV000520748 likely benign not specified 2017-08-30 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.
Color Health, Inc 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 RCV001286924 SCV001473553 uncertain significance none 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112366 SCV000145132 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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