Submissions for variant NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser)

gnomAD frequency: 0.00001  dbSNP: rs373114291

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123078	SCV000166373	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131575	SCV000186583	likely benign	Hereditary cancer-predisposing syndrome	2018-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000479914	SCV000565404	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a history of a Lynch syndrome-associated tumor and/or polyps, breast cancer, and other cancers (Yurgelun et al., 2015; Zhang et al., 2015; Blount et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25980754, 26580448, 29286535, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000131575	SCV000686125	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 474 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), breast cancer (PMID: 29286535, 33471991), as well as in healthy control individuals (PMID: 33471991). This variant has also been identified in 6/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001775084	SCV002012391	uncertain significance	Lynch syndrome 4	2021-09-09	criteria provided, single submitter	clinical testing	The PMS2 c.1420G>T (p.Ala474Ser) missense change has a maximum subpopulation frequency of 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6026976-C-A). This variant is located in exon 11 of the PMS2 gene and data in this region are not considered reliable due to high pseudogene homology. This variant has been reported in an individual with a history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in an individual with a breast cancer and a family history of breast and other cancers (PMID: 29286535). Five of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. Due to high pseudogene homology in this region, variant confirmation by an orthogonal method (e.g. long range PCR) is recommended.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824617	SCV002074367	uncertain significance	not specified	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1420G>T (p.Ala474Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1420G>T has been reported in the literature in individuals affected with Lynch Syndrome, Breast cancer or Osteosarcoma as well as in healthy controls (Yurgelun_2015, Zhang_2015, Blount_2018, Dorling_2021). These reports do 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000131575	SCV002529793	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149840	SCV003837736	uncertain significance	Breast and/or ovarian cancer	2021-06-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479914	SCV004218953	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual with osteosarcoma (PMID: 26580448 (2015)), individuals with breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)), and in unaffected individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000053 (6/113768 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.