ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1927A>G (p.Ser643Gly)

dbSNP: rs80357105
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077502 SCV001161504 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00055
GeneDx RCV000236055 SCV000293185 uncertain significance not provided 2015-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1927A>G at the cDNA level, p.Ser643Gly (S643G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant has been previously published as BRCA1 2046A>G, having been observed in a breast cancer family (Stoppa-Lyonnet 1997). BRCA1 Ser643Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser643Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the DNA binding domain (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser643Gly is pathogenic or benign.
Counsyl RCV000077502 SCV000785055 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2017-03-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000775173 SCV000909358 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001296354 SCV001485315 likely benign Hereditary breast ovarian cancer syndrome 2024-12-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775173 SCV002719843 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-09 criteria provided, single submitter clinical testing The p.S643G variant (also known as c.1927A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1927. The serine at codon 643 is replaced by glycine, an amino acid with similar properties. In a study of 160 women with a family history of breast and/or ovarian cancer, this variant was reported in one family with a history of breast cancer (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30). This variant has also been reported in a female with breast cancer at age 66, who tested negative for a known familial pathogenic BRCA1 mutation (Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan;16:4). This alteration was also classsified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 09;40(9):1557-1578). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sharing Clinical Reports Project (SCRP) RCV000077502 SCV000109302 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2009-02-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077502 SCV000144251 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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