7-6009019-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong
The NM_000535.7(PMS2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
NM_000535.7 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000328 AC: 5AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250222Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135572
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460242Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 726424
GnomAD4 genome 0.0000328 AC: 5AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in patients in the heterozygous state with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Borras et al., 2013; Okkels et al., 2019; Tian et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 19283792, 25512458, 22577899, 32068069, 28466842, 31433215, 31447099, 21376568, 23709753, 20487569, 23012243, 21261604, 27064304, 28514183, 27476653, 26895986, 27435373, 26681312, 29485237, 28491141, 25980754, 31054147, 31491536, 31992580, 34308366, 30787465, 33087929, 18602922) -
PP4, PP5, PM3, PVS1_moderate -
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This variant disrupts the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/128208 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 20487569 (2010)), endometrial cancer (PMID: 23709753 (2013)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 18602922 (2008)). Based on the available information, this variant is classified as pathogenic. -
Lynch syndrome 4 Pathogenic:4
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922]. -
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Lynch syndrome 1 Pathogenic:2Other:1
meets criteria for Class 4 -
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Mismatch repair cancer syndrome 4 Pathogenic:2
Criteria applied: PVS1_STR,PM3,PP4 -
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Lynch syndrome Pathogenic:2
The p.Met1? (c.1A>G) variant in PMS2 has been reported in the heterozygous state in at least 8 individuals with Lynch syndrome-associated cancers and 4 individuals who were referred for clinical genetic testing of germline cancer genes (Talseth-Palmer 2010 PMID: 20487569, Borras 2013 PMID: 23709753, Vaughn 2013 PMID: 23012243, Susswein 2016 PMID: 26681312, Brennan 2017 PMID: 28491141, Tian 2019 PMID: 31054147, Yanus 2020 PMID: 31491536, Wang 2020 PMID: 31992580, Kwong 2020 PMID: 32068069, Singh 2023 PMID: 37296477), including at least one individual with tumour analysis showing loss of PMS2 by immunohistochemistry (IHC). It has also been also reported in the compound heterozygous state in at least 3 individuals with features of constitutional mismatch repair deficiency (CMMRD; Senter 2008 PMID: 18602922, LOVD database) with tumors demonstrating loss of PMS2 expression by IHC. It has also been identified in 0.003% (33/1179848) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an alternative translation initiation codon) are possible. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch Syndrome. Moreover, this variant has been classified as Likely Pathogenic on June 30, 2017 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108326.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Moderate, PM3_Strong, PM2_Supporting. -
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 in exon 4. Exons 1 through 10 of the PMS2 gene encodes a functionally important ATPase domain. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 20487569, 23012243, 23709753, 27064304, 31992580, 32775946). This variant has been observed in trans with pathogenic variants in three unrelated individuals with personal cancer history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). There was no detectable PMS2 protein expression in these individuals. This variant has been identified in 8/281624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions impacting methionine at codon 1 (c.1A>T, c.1A>C, c.2T>C, c.2T>A, c.2T>G, c.3G>A, c.3G>C) are known to be disease-causing (ClinVar variation ID: 142777, 820477, 127788, 182809, 231873, 450786, 957082). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 in exon 4. Exons 1 through 10 of the PMS2 gene encodes a functionally important ATPase domain. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 20487569, 23012243, 23709753, 27064304, 31992580, 32775946). This variant has been observed in trans with pathogenic variants in three unrelated individuals with personal cancer history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). There was no detectable PMS2 protein expression in these individuals. This variant has been identified in 8/281624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions impacting methionine at codon 1 (c.1A>T, c.1A>C, c.2T>C, c.2T>A, c.2T>G, c.3G>A, c.3G>C) are known to be disease-causing (ClinVar variation ID: 142777, 820477, 127788, 182809, 231873, 450786, 957082). Based on the available evidence, this variant is classified as Pathogenic. -
The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the PMS2 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation has been previously identified in 3 probands with early-onset, Lynch syndrome-associated malignancies and tumors demonstrating isolated loss of PMS2 staining by immunohistochemistry (IHC). Of note, all 3 probands were determined to carry the c.1A>G (p.M1?) mutation in conjunction with a pathogenic PMS2 mutation in trans and had a clinically distinct (more severe) phenotype compared to monoallelic PMS2 mutation carriers (Senter et al. Gastroenterology. 2008 Aug;135(2):419-28). This alteration has been reported in individuals with biallelic PMS2 mutations and phenotypes consistent with constitutional mismatch repair deficiency (CMMRD) (Johannesma PC et al. Clin Genet. 2011 Sep;80(3):243-55; Singh AK et al. BMC Med Genomics. 2023 Jun;16(1):126; Ambry internal data). In other studies, this mutation has been identified in multiple patients with Lynch syndrome, including those whose tumors have demonstrated isolated loss of PMS2 by IHC and/or microsatellite instability (Borràs E et al. J. Med. Genet. 2013 Aug; 50(8):552-63; Cadoo KA et al. JCO Precis Oncol. 2019 Apr;3; Wang Q et al. J Med Genet. 2020 07;57(7):487-99). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
PMS2-related disorder Pathogenic:1
The PMS2 c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported along with a second PMS2 pathogenic variant in individuals with early onset (<30 years) colorectal cancer (Senter et al. 2008. PubMed ID: 18602922, Table 3) and has been reported alone, in the heterozygous state, in many individuals with personal and/or family histories of Lynch syndrome cancers (Borràs et al. 2013. PubMed ID: 23709753, Table 1; Brennan et al. 2017. PubMed ID: 28491141, Table 6; Tian et al. 2019. PubMed ID: 31054147, Table S1, Patient EC132; Wang et al. 2020. PubMed ID: 31992580, Table 1). It has also been reported in individuals with breast cancer (Susswein et al. 2015. PubMed ID: 26681312, Table S1; Wang et al. 2020. PubMed ID: 31992580, Table 1). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91323/). Furthermore, multiple variants in PMS2 that result in a start loss have been associated with PMS2-related cancers and are interpreted as likely pathogenic or pathogenic in ClinVar (Human Gene Mutation Database; ClinVar Variation IDs: 142777, 820477, 182809, 127788, 450786). The c.1A>G variant is interpreted as likely pathogenic. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250382 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.1A>G has been reported in the literature in individuals affected with LS but also in unaffected individuals, or in patients with co-occurring pathogenic PMS2 variants (Borras_2013, Senter_2008, Sjursen_2016). In three of these biallelic PMS2 patients the phenotype was more suggestive of constitutional mismatch repair deficiency syndrome (CMMRD) than LS, moreover IHC results demonstrated loss of PMS2 expression in the tumors as well as in the adjacent unaffected tissues. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories and one expert panel (InSight) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic, some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in population databases (rs587779333, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with colorectal cancer, endometrial cancer, and/or individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20487569, 23709753; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91323). For these reasons, this variant has been classified as Pathogenic. -
Mismatch repair cancer syndrome 1 Pathogenic:1
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple patients [PMID 18602922, 23709753, 28491141, 26681312] -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at