Submissions for variant NM_007294.4(BRCA1):c.1005C>A (p.Ser335Arg)

dbSNP: rs876660367

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221259	SCV000277742	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The p.S335R variant (also known as c.1005C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 1005. The serine at codon 335 is replaced by arginine, an amino acid with dissimilar properties. 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.
Invitae	RCV000475154	SCV000549394	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 335 of the BRCA1 protein (p.Ser335Arg). This variant is not present in population databases (gnomAD no frequency). A different variant (c.1124C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 11733976). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 233381). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589343	SCV000698825	uncertain significance	not specified	2021-01-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1005C>A (p.Ser335Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1005C>A in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000221259	SCV001341302	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 335 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000221259	SCV003846236	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).