Submissions for variant NM_007294.4(BRCA1):c.121C>T (p.His41Tyr)

dbSNP: rs1060502353

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704369	SCV000833315	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 41 of the BRCA1 protein (p.His41Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28486781). ClinVar contains an entry for this variant (Variation ID: 580736). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25823446, 30209399). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15168169, 16403807, 20103620, 21725363, 23161852, 24489791, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001184334	SCV001350294	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 41 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the variant to cause loss of protein function in a haploid cell proliferation assay (PMID: 30209399), reduced E3 ligase activity (PMID: 25823446) and disrupted binding to E2 ubiquitin conjugating enzyme (PMID: 16403807). This variant has been reported in five individuals affected with breast cancer (PMID: 28486781, 32733560, 33067490). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same position, p.His41Arg and p.His41Leu, are classified as Pathogenic (Clinvar variation ID: 54166, 230862), suggesting that histidine at this position is important for BRCA1 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000704369	SCV001449162	pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-14	criteria provided, single submitter	clinical testing	Data included in classification: This variant has been reported in one UK case of ovarain cancer, with LOH at 17q on tumour testing. The variant is absent from GNOMAD (PM2_sup), predicted deleterious on multiple in silico tools including REVEL 0.9 (PP3_sup), affects the same amino acid residue as c.122A>G p.(His41Arg) (PM5_mod), with this residue recognised by ENIGMA as of functional importance (PM1_mod). The variant is non-functional on saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, PMID: 30209399) (PS3_Strong). Data not included in classification: Recent (2019-2020) classification as LP/P from Invitae and Color
Ambry Genetics	RCV001184334	SCV002655963	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-03	criteria provided, single submitter	clinical testing	The p.H41Y pathogenic mutation (also known as c.121C>T), located in coding exon 2 of the BRCA1 gene, results from a C to T substitution at nucleotide position 121. The histidine at codon 41 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Lolas Hamameh S et al. Int. J. Cancer, 2017 Aug;141:750-756; Abdel-Razeq H et al. J Oncol, 2020 Jul;2020:8362179). This alteration was shown to have severely defective E3 ubiquitin ligase activity, however it maintained intact BARD1 binding capability (Starita LM et al. Genetics, 2015 Jun;200:413-22). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant affects a known zinc binding motif which is predicted to disrupt protein folding (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A., 2003 May;100:5646-51). Two other alterations at the same codon, p.H41R (c.122A>G) and p.H41N (c.121C>A), have been shown to be functionally deleterious in multiple functional assays (Morris JR et al. Hum. Mol. Genet. 2006 Feb; 15(4):599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb; 70(3):988-95; Towler WI et al. Hum. Mutat. 2013 Mar; 34(3):439-45; Caleca L et al. Cancers (Basel), 2019 Jan;11; Starita LM et al. Genetics, 2015 Jun;200:413-22; Starita LM et al. Am. J. Hum. Genet., 2018 Oct;103:498-508; Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV001077001	SCV004211741	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-08-30	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696983	SCV005199761	likely pathogenic	not provided	2023-05-29	criteria provided, single submitter	clinical testing
GeneDx	RCV004696983	SCV005326227	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired BARD1 binding and E3 auto-ubiquitination, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 25823446, 30209399, 33087888); Observed in individuals with breast cancer (PMID: 32733560, 33067490, 28486781, 34597585, 37901051, 34290354); This variant was classified as pathogenic based on a multifactorial model incorporating family history, pathology, and co-segregation (PMID: 34597585); 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 c.240C>T; This variant is associated with the following publications: (PMID: 30209399, 32733560, 33067490, 33087888, 31131967, 25823446, 20104584, 24389207, 8944023, 34290354, 28486781, 34597585, 37901051)
All of Us Research Program, National Institutes of Health	RCV004802395	SCV005428673	likely pathogenic	BRCA1-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 41 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown the variant to cause loss of protein function in a haploid cell proliferation assay (PMID: 30209399), reduced E3 ligase activity (PMID: 25823446) and disrupted binding to E2 ubiquitin conjugating enzyme (PMID: 16403807). This variant has been reported in at least three individuals affected with breast cancer that are described as high-risk or have a family history of breast and ovarian cancer (PMID: 28486781, 32733560, 33067490). Other missense variants at this codon have been reported as (likely) disease-causing in ClinVar (variation ID: 54166, 868161, 230862, 409353), suggesting that the conserved histidine is functionally important. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Brotman Baty Institute, University of Washington	RCV001077001	SCV001242858	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001077001	SCV003927204	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	BRCA1 (p.His41Tyr): This sequence change replaces histidine with tyrosine at codon 41 of the BRCA1 protein (p.His41Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (gnomAD exomes, gnomAD genomes). This variant has been observed in an individual affected with breast cancer (PMID: 28486781). ClinVar contains an entry for this variant (Variation ID: 580736). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 4 submissions, 8 publications (15168169, 16403807, 20103620, 21725363, 23161852 and 3 more) and no conflicts. This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 30209399). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15168169, 24489791, 16403807, 23161852, 20103620, 21725363, 30209399). Therefore, this variant has been classified as Pathogenic.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV001077001	SCV005061306	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control