ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.608C>A (p.Thr203Asn) (rs398122547)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471187 SCV000549867 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 203 of the BRCA2 protein (p.Thr203Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs398122547, ExAC 0.001%). This variant has been observed in trans (on the opposite chromosome) from a pathogenic variant in BRCA2 in an unaffected individual (Invitae). Considering that biallelic pathogenic variants are expected to be found in an individual affected with Fanconi anemia, this evidence indicates that this variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 91437). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
GeneDx RCV000758918 SCV000567749 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.608C>A at the cDNA level, p.Thr203Asn (T203N) at the protein level, and results in the change of a Threonine to an Asparagine (ACC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 836C>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Thr203Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr203Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509879 SCV000608010 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing The p.T203N variant (also known as c.608C>A), located in coding exon 6 of the BRCA2 gene, results from a C to A substitution at nucleotide position 608. The threonine at codon 203 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758918 SCV000887864 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000509879 SCV000905901 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000076954 SCV001269109 uncertain significance Breast-ovarian cancer, familial 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001113535 SCV001271315 uncertain significance Fanconi anemia, complementation group D1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sharing Clinical Reports Project (SCRP) RCV000076954 SCV000108751 uncertain significance Breast-ovarian cancer, familial 2 2012-09-04 no assertion criteria provided clinical testing

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