Submissions for variant NM_000535.7(PMS2):c.11C>G (p.Ala4Gly)

gnomAD frequency: 0.00004  dbSNP: rs745361721

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214339	SCV000276758	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The c.11C>G variant (also known as p.A4G), located in coding exon 1 of the PMS2 gene, results from a C to G substitution at nucleotide position 11. The alanine at codon 4 is replaced by glycine, an amino acid with similar properties. The p.A4G alteration was identified in an Icelandic colorectal cancer cohort in an individual with normal mismatch repair protein staining via immunohistochemistry (IHC) and in another individual with MLH1 promoter hypermethylation, but the nucleotide numbering for this variant was not provided (Haraldsdottir S et al. Nat Commun. 2017 05;8:14755). This alteration was also identified in an individual diagnosed with pancreatic cancer (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). Additionally, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000657052	SCV000279428	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Located in the critical ATPase domain (Guarn et al., 2001); Observed in individuals with colon cancer which demonstrated normal immunohistochemistry or MLH1 hypermethylation, in unaffected controls, and in individual(s) with pancreatic cancer (Grant et al., 2015; Haraldsdottier et al., 2017); This variant is associated with the following publications: (PMID: 25479140, 11574484, 32133419, 28466842)
Invitae	RCV000230374	SCV000285051	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4 of the PMS2 protein (p.Ala4Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs745361721, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer and pancreatic cancer (PMID: 25479140, 28466842). ClinVar contains an entry for this variant (Variation ID: 232589). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in partial exon 1 deletion and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Color Diagnostics, LLC DBA Color Health	RCV000214339	SCV000686105	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 4 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may create an alternative splice donor site 13 basepair upstream of the reference splice donor site, which has been confirmed by an RNA study to affect some RNA transcripts (PMID: 32133419). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 28466842). One of the tumors was found to have normal PMS2 protein expression via immunohistochemistry analysis, and another had MLH1 and PMS2 loss but also demonstrated hypermethylated MLH1 promoter. This tumor data suggests that PMS2 expression is not significantly disrupted. This variant has also been reported in individuals affected with colorectal cancer or colon polyps (PMID: 31422818), pancreatic cancer (PMID: 25479140), prostate cancer (PMID: 32832836), and breast cancer (PMID: 32133419, 33471991), as well as healthy individuals (PMID: 33471991). This variant has been identified in 3/250258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the experimental data suggest that the variant may impact RNA splicing, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222258	SCV000731352	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Ala4Gly variant in PMS2 has not been previously reported in individuals wi th colorectal cancer, but has been identified in 1/11544 Latino chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 45361721). While computational pathogenicity prediction tools and conservation a nalysis suggest that the p.Ala4Gly variant may not impact the protein, this vari ant is predicted to create a novel splice site. However, the accuracy of these tools is unknown and therefore this information is not predictive enough to dete rmine or rule out pathogenicity. In summary, the clinical significance of the p. Ala4Gly variant is uncertain.
Counsyl	RCV000662535	SCV000785108	uncertain significance	Lynch syndrome 4	2017-04-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662535	SCV001322572	uncertain significance	Lynch syndrome 4	2018-01-13	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657052	SCV002047021	uncertain significance	not provided	2021-04-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000214339	SCV002529767	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662535	SCV004019840	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657052	SCV004223995	uncertain significance	not provided	2023-01-16	criteria provided, single submitter	clinical testing	PP3, PM2
CeGaT Center for Human Genetics Tuebingen	RCV000657052	SCV004702090	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PMS2: PM2:Supporting, PP3, PS3:Supporting, PS4:Supporting
All of Us Research Program, National Institutes of Health	RCV003997985	SCV004842186	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 4 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may create an alternative splice donor site 13 basepair upstream of the reference splice donor site, which has been confirmed by an RNA study to affect some RNA transcripts (PMID: 32133419). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer, although the individual was found to also have normal PMS2 protein expression and hypermethylated MLH1 promoter in the tumor (PMID: 28466842). The primary cause of disease in this individual is not clear. This variant has also been reported in individuals affected with pancreatic cancer (PMID: 25479140) and breast cancer (PMID: 32133419). This variant has been identified in 3/250258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the experimental data suggest that the variant may impact RNA splicing, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354151	SCV001548694	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ala4Gly variant was identified in the literature with carrier frequency in Iceland of 0.04 and odds ratio for CRC of 2.64 (95%CI:0.62-11.2, Haraldsdottir 2017). The variant was also identified in dbSNP (ID: rs745361721) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and three other submitters), and in Insight Hereditary Tumors database (1x). The variant was not identified in COGR, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 3 of 245352 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33576 chromosomes (freq: 0.00003), European in 2 of 110948 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala4 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.