Submissions for variant NM_000059.4(BRCA2):c.1627C>T (p.His543Tyr)

dbSNP: rs80358446

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166042	SCV000216803	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-08	criteria provided, single submitter	clinical testing	The p.H543Y variant (also known as c.1627C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1627. The histidine at codon 543 is replaced by tyrosine, an amino acid with similar properties. 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.
GeneDx	RCV000485437	SCV000571832	uncertain significance	not provided	2016-09-27	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1627C>T at the cDNA level, p.His543Tyr (H543Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 1855C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His543Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His543Tyr occurs at a position that is not conserved and is not located in a known functional domain (Cole 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 His543Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000166042	SCV000906027	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 543 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast and/or ovarian cancer (PMID: 31825140). 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	RCV001193751	SCV001362832	uncertain significance	not specified	2019-07-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1627C>T (p.His543Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250880 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1627C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347556	SCV001541823	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 543 of the BRCA2 protein (p.His543Tyr). 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. 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 BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 186449). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 31825140).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166042	SCV003851529	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).