Submissions for variant NM_007294.4(BRCA1):c.535T>C (p.Tyr179His)

gnomAD frequency: 0.00001  dbSNP: rs587781761

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129980	SCV000184804	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The p.Y179H variant (also known as c.535T>C), located in coding exon 6 of the BRCA1 gene, results from a T to C substitution at nucleotide position 535. The tyrosine at codon 179 is replaced by histidine, an amino acid with similar properties. This alteration was identified in a male diagnosed with breast cancer (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000657128	SCV000294070	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Observed in an individual undergoing BRCA1/2 testing and in a male with breast cancer (Judkins et al., 2005; Rizzolo et al., 2019); 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 654T>C; This variant is associated with the following publications: (PMID: 26295337, 29884841, 32377563, 20215511, 9788437, 30613976, 31853058, 16267036, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239018	SCV000296441	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-11	criteria provided, single submitter	clinical testing
Invitae	RCV000464515	SCV000549365	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 179 of the BRCA1 protein (p.Tyr179His). This variant is present in population databases (rs587781761, gnomAD 0.002%). This missense change has been observed in individual(s) with a high risk for breast and ovarian cancer and/or breast cancer (PMID: 16267036, 30613976). ClinVar contains an entry for this variant (Variation ID: 141458). 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 expected to disrupt BRCA1 protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129980	SCV000683304	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 179 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/53461 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006563) and among individuals who underwent BRCA1 mutation screening (PMID: 16267036). This variant also has been reported to have a tumor pathology likelihood ratio for pathogenicity of 0.2938 (PMID: 31131967). This variant has been identified in 2/251454 chromosomes 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.
Sema4, Sema4	RCV000129980	SCV002537847	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
Baylor Genetics	RCV000239018	SCV004215016	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236482	SCV000591278	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Tyr179His variant was not identified in the literature, nor was it identified in the HGMD, UMD, COSMIC, BIC or LOVD databases. The UMD database identified another variant at this amino acid position (p.Tyr179Cys (c.536A>G)) that was observed in 4 (of 29) individuals as co-occurring with a second pathogenic variant in BRCA1 or BRCA2, increasing the likelihood that an alteration to this residue may not have clinical significance. The p.Tyr179 residue is conserved in mammals but not in all lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD) suggest that the p.Tyr179His variant may impact the protein; however, this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV000239018	SCV004228317	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)