ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5014T>C (p.Tyr1672His) (rs781671762)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222124 SCV000279737 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5014T>C at the cDNA level, p.Tyr1672His (Y1672H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA2 5242T>C. This variant was observed in 1/222 Hispanic white individuals with early onset breast cancer (Lee 2008); however BRCA2 Tyr1672His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr1672His occurs at a position that is not conserved and is located in the BRC 5 repeat domain that interacts with POLH and within the RAD51 binding domain (Roy 2012). 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 Tyr1672His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000560184 SCV000635421 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1672 of the BRCA2 protein (p.Tyr1672His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs781671762, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 18284688). ClinVar contains an entry for this variant (Variation ID: 234726). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000586736 SCV000694819 uncertain significance not provided 2016-01-22 criteria provided, single submitter clinical testing Variant summary: This c.5014T>C variant affects a non-conserved nucleotide, resulting in amino acid change from Tyr to His. 3/5 in-silico tools predict this variant to be benign. This variant was found in 4/118512 chromosomes from ExAC at a frequency of 0.0000338. It was exclusively found in Latino (i.e. Hispanic White) cohort at frequency of 0.00034 (4/11484 chromosomes). This frequency is lower than the maximal expected frequency of a pathogenic allele (0.0007503) in this gene. The variants allele frequency in breast cancer patient cohort of Hispanic White was 0.0023 (1/444 chromosomes) (Lee_2008). It is possible that this variant is an ethnic- specific rare functional polymorphism, however further investigation needed to support this proposition. Taken together, the variant was classified as VUS, until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586736 SCV000887833 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing

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