ClinVar Genomic variation as it relates to human health

This variant causes a G>A nucleotide substitution at the +1 position of intron 4 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change affects a donor splice site in intron 4 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 26689913, 36451132). ClinVar contains an entry for this variant (Variation ID: 234652). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The c.353+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the PMS2 gene. This alteration has been identified in several probands whose Lynch syndrome associated tumors demonstrated isolated loss of PMS2 staining on immunohistochemistry (IHC) (Ambry internal data). This alteration has been reported in a head and neck squamous cell carcinoma cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). Another alteration impacting the same donor site (c.353G>A) has been shown to have a similar impact on splicing and has also been identified in individuals whose Lynch syndrome-associated tumors demonstrated isolated loss of PMS2 staining on IHC (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Identified at 55% allele fraction in a small round cell lung tumor demonstrating high microsatellite instability and mutation burden (PMID: 36090644); This variant is associated with the following publications: (PMID: 21376568, 16199547, 24362816, 26689913, 36451132, 36090644)

Variant summary: PMS2 c.353+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 234822 control chromosomes (gnomAD). c.353+1G>A has been reported in the literature in an individual affected with head and neck squamous cell carcinoma (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The PMS2 c.353+1G>A intronic change results in a G to A substitution at the +1 position of intron 4 of the PMS2 gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or abnormal protein product. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). It has been reported in one individual with head and neck squamous cell carcinoma (PMID: 26689913). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as likely pathogenic.

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.