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

Total submissions: 8

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