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

dbSNP: rs764640893

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481470	SCV000568971	uncertain significance	not provided	2019-11-07	criteria provided, single submitter	clinical testing	Previously reported as a somatic variant in gastric cancer (Park et al., 2011), but has not been reported in the germline to our knowledge; Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 164 amino acids are lost and replaced with 5 incorrect amino acids, but clinical significance is uncertain; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards 2015); This variant is associated with the following publications: (PMID: 21240073)
Invitae	RCV000481470	SCV001216323	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with a complex clinical presentation including dysmorphic features, skeletal and muscular abnormalities, and renal insufficiency (PMID: 32860008). ClinVar contains an entry for this variant (Variation ID: 420244). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Leu117Phefs*6) in the XRCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acid(s) of the XRCC2 protein.
Centogene AG - the Rare Disease Company	RCV001251190	SCV001426576	likely pathogenic	Fanconi anemia complementation group U		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455921	SCV002613061	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	The c.350dupT variant, located in coding exon 3 of the XRCC2 gene, results from a duplication of T at nucleotide position 350, causing a translational frameshift with a predicted alternate stop codon (p.L117Ffs*6). This alteration occurs at the 3' terminus of the XRCC2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 164 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.