Submissions for variant NM_007294.4(BRCA1):c.1897C>T (p.Pro633Ser)

gnomAD frequency: 0.00001  dbSNP: rs80356902

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085614	SCV000075639	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000077500	SCV000488059	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510032	SCV000607922	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The p.P633S variant (also known as c.1897C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1897. The proline at codon 633 is replaced by serine, an amino acid with similar 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.
Color Diagnostics, LLC DBA Color Health	RCV000510032	SCV000682999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 633 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 been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001026). A multifactorial analysis has reported likelihood ratios of pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.102 and 0.458, 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510032	SCV003849658	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).
GeneDx	RCV000656639	SCV004025534	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Observed in an individual that underwent BRCA1 and BRCA2 genetic testing for a personal or family history suggestive of Hereditary Breast and Ovarian Cancer (Judkins et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2016C>T; This variant is associated with the following publications: (PMID: 16267036, 23704879, 15235020, 15343273, 31131967)
PreventionGenetics, part of Exact Sciences	RCV004554653	SCV004120407	uncertain significance	BRCA1-related disorder	2022-09-30	criteria provided, single submitter	clinical testing	The BRCA1 c.1897C>T variant is predicted to result in the amino acid substitution p.Pro633Ser. Computational analyses suggest that this variant, and another variant impacting the same amino acid [c.1897C>A (p.Pro633Thr)], lead to altered phosphorylation motifs in BRCA1 (Table 1, Tram et al. 2013. PubMed ID: 23704879). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations regarding its pathogenic in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/54387/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656639	SCV004222577	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with a personal or family history of breast/ovarian cancer (PMID: 16267036 (2005)). It has also been reported in an individual with breast cancer and in an unaffected control in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000077500	SCV004818260	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 633 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 been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001026). A multifactorial analysis has reported likelihood ratios of pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.102 and 0.458, 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.
Sharing Clinical Reports Project (SCRP)	RCV000077500	SCV000109299	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077500	SCV000144238	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2001-10-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656639	SCV000778766	uncertain significance	not provided	2018-02-26	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077500	SCV004244109	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-02	no assertion criteria provided	clinical testing