Submissions for variant NM_007294.4(BRCA1):c.661G>T (p.Ala221Ser)

gnomAD frequency: 0.00004  dbSNP: rs80357088

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703433	SCV000210081	likely benign	not provided	2018-10-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15235020, 21309043, 25682074, 16267036, 15385441, 10923033)
Ambry Genetics	RCV000165438	SCV000216167	likely benign	Hereditary cancer-predisposing syndrome	2018-11-08	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.
Counsyl	RCV000031271	SCV000489036	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200971	SCV000600432	uncertain significance	not specified	2017-07-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165438	SCV000683341	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 221 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been observed in 5/60461 cases and 2/53459 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; Leiden Open Variation Database DB-ID BRCA1_000102) (PMID 33471991). This variant has been identified in 5/281660 chromosomes 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.
Invitae	RCV001498329	SCV001703079	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200971	SCV001774462	likely benign	not specified	2023-04-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.661G>T (p.Ala221Ser) results in a 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 1.6e-05 in 250732 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.661G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5284_5284delA, p.Arg1762Glyfs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000031271	SCV004818427	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 221 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been observed in 5/60461 cases and 2/53459 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; Leiden Open Variation Database DB-ID BRCA1_000102) (PMID 33471991). This variant has been identified in 5/281660 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000031271	SCV000053876	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2013-01-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031271	SCV000145647	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing