Submissions for variant NM_007294.4(BRCA1):c.3902G>A (p.Ser1301Asn)

gnomAD frequency: 0.00001  dbSNP: rs1057519496

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586928	SCV000565779	likely benign	not provided	2019-09-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27135926)
Ambry Genetics	RCV000509773	SCV000608207	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	The p.S1301N variant (also known as c.3902G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3902. The serine at codon 1301 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416523	SCV000635929	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265753	SCV000699084	uncertain significance	not specified	2022-05-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3902G>A (p.Ser1301Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251170 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3902G>A has not, to our knowledge, been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome nor has experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four laboratories classified the variant as VUS and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586928	SCV001133571	uncertain significance	not provided	2020-03-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509773	SCV001348245	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1301 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002439). A multifactorial analysis has reported likelihood ratios for pathogenicity based on family history and co-occurrence with a pathogenic covariant at 0.0961 and 1.0331, respectively (PMID: 31131967). This variant has been identified in 1/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509773	SCV003849494	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV003493568	SCV004817728	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1301 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002439). A multifactorial analysis has reported likelihood ratios for pathogenicity based on family history and co-occurrence with a pathogenic covariant at 0.0961 and 1.0331, respectively (PMID: 31131967). This variant has been identified in 1/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
BRCAlab, Lund University	RCV003493568	SCV004244021	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing