ClinVar Miner

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

dbSNP: rs1060502353
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704369 SCV000833315 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-09 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). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-15 criteria provided, single submitter clinical testing The p.H41Y variant (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 was identified in a Palestinian woman with a personal history of breast cancer diagnosed at age 54 who also had a sister diagnosed with breast cancer at age 68 (Lolas Hamameh S et al. Int. J. Cancer, 2017 Aug;141:750-756). 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). 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). A less-severe substitution of arginine at this amino acid position is a well-documented pathogenic mutation (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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics RCV001077001 SCV004211741 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-08-30 criteria provided, single submitter clinical testing
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.

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