Submissions for variant NM_007294.4(BRCA1):c.3800T>C (p.Leu1267Ser)

gnomAD frequency: 0.00001  dbSNP: rs587782190

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130824	SCV000185720	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	The p.L1267S variant (also known as c.3800T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 3800. The leucine at codon 1267 is replaced by serine, an amino acid with dissimilar properties. In a cohort of 300 deceased patients, who underwent whole genome sequencing for 60 autosomal dominant cancer predisposition genes, this variant was detected and classified as likely benign by the authors. However, the specific phenotype of the patient(s) with this alteration was not reported (He KY et al. PLoS ONE, 2016 Dec;11:e0167847). This alteration has been reported as neutral in high-throughput complementation assays performed in mouse embryonic stem cells (Bouwman P. et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P. et al. Clin Cancer Res. 2020 09;26(17):4559-4568). 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.
GeneDx	RCV000589536	SCV000210156	uncertain significance	not provided	2019-01-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3800T>C at the cDNA level, p.Leu1267Ser (L1267S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). Functional studies by Bouwman et al. (2013) suggest that BRCA1 Leu1267Ser may be a neutral variant based on insensitivity to cisplatin and ability to support growth similar to controls in BRCA1-deficient mouse embryonic stem cells. BRCA1 Leu1267Ser was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Leu1267Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000460978	SCV000549344	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130824	SCV000688453	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 1267 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). Functional studies have reported that this variant does not impact on BRCA1 function in cisplatin and Olaparib sensitivity and homology-directed repair assays using mouse Brca1-deficient embryonic stem cells (PMID: 23867111, 32546644). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001533). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on tumor pathology of 0.21 (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589536	SCV000699074	uncertain significance	not provided	2016-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589536	SCV000888900	uncertain significance	not provided	2017-08-26	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000460978	SCV001737436	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-06-10	criteria provided, single submitter	clinical testing	The BRCA1 c.3800T>C (p.Leu1267Ser) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/ ). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4). Functional studies have shown that this change can rescue the proliferation defect of Brca1-deficient mouse embryonic stem cells similar to wild-type and also decrease sensitivity to cisplatin, suggesting that this change does not affect protein function (BS3_Supporting; PMID: 23867111). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BS3_Supporting, BP4.
CeGaT Center for Human Genetics Tuebingen	RCV000589536	SCV001747805	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130824	SCV003846271	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).