Submissions for variant NM_007294.4(BRCA1):c.4417T>C (p.Ser1473Pro)

gnomAD frequency: 0.00001  dbSNP: rs398122686

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476060	SCV000549349	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of Hereditary Breast and Ovarian Cancer Syndrome (PMID: 23613828). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23613828). 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: 91630). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1473 of the BRCA1 protein (p.Ser1473Pro).
Ambry Genetics	RCV000566648	SCV000660989	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-13	criteria provided, single submitter	clinical testing	The p.S1473P variant (also known as c.4417T>C), located in coding exon 12 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4417. The serine at codon 1473 is replaced by proline, an amino acid with similar properties. In one study, this variant was reported in two families with Hereditary Breast and Ovarian Cancer syndrome; however, this variant demonstrated intact transcriptional activity comparable to the wild-type BRCA1 protein in a transcription activation assay (Quiles F et al. PLoS ONE 2013 April; 8(4):e61302). This amino acid position is 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.
Counsyl	RCV000077147	SCV000785097	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566648	SCV000909027	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 1473 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). A functional study has reported that this variant does not impact BRCA1 function in a transcription activation assay (PMID: 23613828). This variant has been reported in an individual suspected of hereditary breast and ovarian cancer (PMID: 23613828). A multifactorial analysis has reported family history, tumor pathology and co-segregation likelihood ratios for pathogenicity of 0.14, 0.003 and 1.195, respectively (PMID: 34597585). 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.
GeneDx	RCV001753482	SCV001997233	uncertain significance	not provided	2019-12-16	criteria provided, single submitter	clinical testing	Observed in individuals suspected of Hereditary Breast and Ovarian Cancer Syndrome (Quiles 2013); Published functional studies demonstrate no damaging effect: Transcriptional activation activity similar to wild-type (Quiles 2013); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as c.4536T>C; This variant is associated with the following publications: (PMID: 23613828)
MGZ Medical Genetics Center	RCV003607232	SCV004543873	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
Sharing Clinical Reports Project (SCRP)	RCV000077147	SCV000108944	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-30	no assertion criteria provided	clinical testing