ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3574C>T (p.Pro1192Ser)

gnomAD frequency: 0.00001  dbSNP: rs754014157
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001176483 SCV001340478 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-15 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 1192 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. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250866 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001222553 SCV001394657 uncertain significance Hereditary breast ovarian cancer syndrome 2021-10-04 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1192 of the BRCA1 protein (p.Pro1192Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs754014157, ExAC 0.005%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV001176483 SCV002618051 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-24 criteria provided, single submitter clinical testing The p.P1192S variant (also known as c.3574C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3574. The proline at codon 1192 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001176483 SCV003848470 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).

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