Submissions for variant NM_007294.4(BRCA1):c.3581C>T (p.Thr1194Ile)

dbSNP: rs80357290

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223601	SCV000274923	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-23	criteria provided, single submitter	clinical testing	The p.T1194I variant (also known as c.3581C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3581. The threonine at codon 1194 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265584	SCV000699042	uncertain significance	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3581C>T (p.Thr1194Ile) 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 250882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3581C>T has been reported in the literature in individuals with Breast and/or Ovarian Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000223601	SCV000909300	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1194 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. A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.0331 and 0.2775 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has not been identified 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	RCV001367738	SCV001564100	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000223601	SCV003848414	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112122	SCV000144794	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112122	SCV000297601	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-15	no assertion criteria provided	clinical testing