ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.350dup (p.Leu117fs) (rs764640893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481470 SCV000568971 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing This duplication of one nucleotide in XRCC2 is denoted c.350dupT at the cDNA level and p.Leu117PhefsX6 (L117FfsX6) at the protein level. The normal sequence, with the base that is duplicated in braces, is ATTTTTTT[T]GGTG. The duplication causes a frameshift, which changes a Leucine to a Phenylalanine at codon 117, and creates a premature stop codon at position 6 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 164 amino acids are replaced by five incorrect ones. Although this variant has not, to our knowledge, been reported as a germline finding in the literature, it has been identified as a somatic variant in a gastric tumor demonstrating high microsatellite instability and described as XRCC2 c.351dupT using alternate nomenclature (Park 2011). This variant is predicted to cause loss of normal protein function through protein truncation, disrupting the ATPase domain (Kim 2011). Based on currently available evidence, we consider XRCC2 c.350dupT to be likely pathogenic.
Invitae RCV000481470 SCV001216323 uncertain significance not provided 2019-02-26 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 3 of the XRCC2 mRNA (c.350dupT), causing a frameshift at codon 117. This creates a premature translational stop signal in the last exon of the XRCC2 mRNA (p.Leu117Phefs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated XRCC2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with XRCC2-related disease. ClinVar contains an entry for this variant (Variation ID: 420244). Experimental studies have shown that a different variant (c.350delT) with a similar protein effect as observed here (p.Leu117fs) has reduced function compared to wild type but the effect is mild and not as strong as other truncating or frame-shifting variants in the same region (PMID: 20189471, 27233470). 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.
Centogene AG - the Rare Disease Company RCV001251190 SCV001426576 likely pathogenic Fanconi anemia, complementation group U criteria provided, single submitter clinical testing

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