Submissions for variant NM_007294.4(BRCA1):c.4333C>A (p.Pro1445Thr)

dbSNP: rs876660684

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219259	SCV000278314	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The p.P1445T variant (also known as c.4333C>A), located in coding exon 11 of the BRCA1 gene, results from a C to A substitution at nucleotide position 4333. The proline at codon 1445 is replaced by threonine, an amino acid with highly 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.
GeneDx	RCV000255891	SCV000321434	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4452C>A; This variant is associated with the following publications: (PMID: 29884841, 32377563, 15343273, 22737296)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781006	SCV000918754	uncertain significance	not specified	2018-07-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4333C>A (p.Pro1445Thr) results in a non-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 4.1e-06 in 246144 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.4333C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from a clinical diagnostic laboratories (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	RCV000219259	SCV001353876	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1445 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251364 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	RCV001854709	SCV002259305	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-11	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 233854). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1445 of the BRCA1 protein (p.Pro1445Thr).
Fulgent Genetics, Fulgent Genetics	RCV002485434	SCV002793226	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998582	SCV004817680	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1445 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251364 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.