Submissions for variant NM_000059.4(BRCA2):c.4981T>C (p.Tyr1661His)

dbSNP: rs730881535

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160081	SCV000210344	uncertain significance	not provided	2017-06-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4981T>C at the cDNA level, p.Tyr1661His (Y1661H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 5209T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr1661His was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr1661His occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Tyr1661His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000772753	SCV000906097	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 1661 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 at high risk for pancreatic cancer (PMID: 30883245). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850259	SCV002278182	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-06	criteria provided, single submitter	clinical testing	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: 182213). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1661 of the BRCA2 protein (p.Tyr1661His).
Ambry Genetics	RCV000772753	SCV002643499	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-24	criteria provided, single submitter	clinical testing	The p.Y1661H variant (also known as c.4981T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 4981. The tyrosine at codon 1661 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in 2/345 individuals at high risk for pancreatic cancer who tested negative for germline mutations in pancreatic susceptibility genes (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772753	SCV003852257	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).