ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.11C>G (p.Ala4Gly) (rs745361721)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214339 SCV000276758 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing The p.A4G variant (also known as c.11C>G), 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). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site that is 13 base pairs upstream from the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000657052 SCV000279428 uncertain significance not provided 2020-12-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in individuals with colon cancer which demonstrated normal immunohistochemistry or MLH1 hypermethylation, as well as in unaffected controls (Haraldsdottier 2017); This variant is associated with the following publications: (PMID: 28466842, 32133419)
Invitae RCV000230374 SCV000285051 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 4 of the PMS2 protein (p.Ala4Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs745361721, ExAC 0.009%). This variant has been observed in individuals affected with colorectal cancer and pancreatic cancer (PMID: 28466842, 25479140). ClinVar contains an entry for this variant (Variation ID: 232589). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 Health, Inc RCV000214339 SCV000686105 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-31 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.
Laboratory for Molecular Medicine, Partners HealthCare 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 Hereditary nonpolyposis colorectal cancer type 4 2017-04-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662535 SCV001322572 uncertain significance Hereditary nonpolyposis colorectal cancer type 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.
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.

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