Submissions for variant NM_007294.4(BRCA1):c.626C>T (p.Pro209Leu)

dbSNP: rs201596327

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473299	SCV000549303	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the BRCA1 protein (p.Pro209Leu). This variant is present in population databases (rs201596327, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer as well as healthy individuals (PMID: 19016756, 27124784, 28179634, 28364669, 30287823). ClinVar contains an entry for this variant (Variation ID: 409315). 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. 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	RCV000563599	SCV000668504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.P209L variant (also known as c.626C>T), located in coding exon 8 of the BRCA1 gene, results from a C to T substitution at nucleotide position 626. The proline at codon 209 is replaced by leucine, an amino acid with similar properties. In one study, this alteration was reported with a carrier frequency of 11 in 7051 unselected breast cancer patients and 20 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant has also been reported in additional Japanese and Korean patients with personal and/or family histories of breast and/or ovarian cancer (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8; Park KS et al. Genet. Med. 2016 Dec;18:1250-1257; Ahmadloo S et al. J. Hum. Genet. 2017 Apr;62:561-567; Ryu JM et al. Breast. 2017 Jun;33:109-116; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457). 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.
Color Diagnostics, LLC DBA Color Health	RCV000563599	SCV000688649	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590268	SCV000699281	uncertain significance	not specified	2020-08-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.626C>T (p.Pro209Leu) 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 allele was found at a frequency of 8e-05 in 276206 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.001), allowing no conclusion about variant significance. However, this variant has been reported at a frequency of 0.0013 in Japanese population (Ahmadloo_2017). c.626C>T has been reported in the literature in individuals affected with breast and/or ovarian cancer (Ahmadloo_2017, Nakamura_2013, Park_2016, Ryu_2017, Sugano_2008). 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 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283910	SCV001469403	uncertain significance	not provided	2019-12-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401478	SCV004103331	uncertain significance	BRCA1-related condition	2023-03-27	criteria provided, single submitter	clinical testing	The BRCA1 c.626C>T variant is predicted to result in the amino acid substitution p.Pro209Leu. This variant has been reported in individuals with breast and/or ovarian cancer (Ahmadloo et al. 2017. PubMed ID: 28179634; Ryu et al. 2017. PubMed ID: 28364669; Arai et al. 2018. PubMed ID: 29176636; Supplementary Data File S1, Kim et al. 2020. PubMed ID: 31907386). Of note this variant has also been reported in control populations (Momozawa et al. 2018. PubMed ID: 30287823) and is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41247907-G-A). This variant is also reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/409315/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.