7-6005918-C-T

Variant names:

• chr7-6005918-C-T
• rs121434629
• NM_000535.7:c.137G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000535.7(PMS2):​c.137G>A​(p.Ser46Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,548 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.54

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-6005918-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-6005918-C-T is Pathogenic according to our data. Variant chr7-6005918-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.137G>A	p.Ser46Asn	missense_variant	Exon 2 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.137G>A	p.Ser46Asn	missense_variant	Exon 2 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245780 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458548 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000171 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 12, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 24, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in a patient with a personal history of a sebaceous adenoma and a family history of colon cancer (PMID: 25006859); Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (PMID: 24027009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34873870, 33259954, 28125078, 25871441, 26940435, 9607916, 18602922, 26866578, 21182953, 31992580, 31658756, 30155321, 28286799, 22577899, 21239990, 21376568, 18094436, 16144131, 25006859, 18273873, 24027009, 11574484) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 46 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant protein causes significantly decreased mismatch repair activity in an in vitro assay (PMID: 24027009). This variant has been reported in an individual with sebaceous neoplasm and family history of colorectal cancer (PMID: 25006859) and in multiple other individuals with personal and family history of Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000552059.6, SCV002699807.1). This variant has been observed in an individual affected with constitutional mismatch repair deficiency in compound heterozygous state with another disease-causing variant in the same gene (PMID: 18273873). In addition, a different variant affecting the same codon (p.Ser46Ile) is considered to be disease-causing (ClinVar variation ID: 9245), suggesting that serine at this position is important for PMS2 protein function. This variant has been identified in 2/245780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Oct 30, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S46N variant (also known as c.137G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 137. The serine at codon 46 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified likely in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome, whose Lynch syndrome-associated tumor and normal tissue demonstrated loss of PMS2 expression by immunohistochemistry; the tumor also displayed high frequency microsatellite instability (Jackson CC et al. Pediatr Blood Cancer 2008 Jun; 50(6):1268-70). In an in vitro study, this alteration displayed less than 10% relative repair efficiency compared to the wild-type control, a level similar to the repair-deficient control (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). Based on internal structural analysis, p.S46N is more disruptive to the structure near the ATP-binding region than a pathogenic variant at the same position (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Apr 15, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 46 of the PMS2 protein (p.Ser46Asn). This variant is present in population databases (rs121434629, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 18273873, 25006859, 26866578; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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: 91301). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 24027009). This variant disrupts the p.Ser46 amino acid residue in PMS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22577899, 23709753). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4 Pathogenic:1

Sep 18, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24027009]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25006859, 18602922, 18273873]. -

Endometrial carcinoma Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Ser46Asn variant was identified in 2 of 370 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Senter 2008, Everett 2014). The variant was also identified in dbSNP (ID: rs121434629) as "With Pathogenic allele", ClinVar (classified as uncertain significance by InSight; as likely pathogenic by Invitae; and as pathogenic by Mayo Clinic), GeneInsight-COGR, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors database (4x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 2 of 240416 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 107732 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser46 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. The variant was reported as a biallelic gene mutation, identified with the PMS2 c.137G>T mutation in an individual with sigmoid adenocarcinoma; the tumour had high microsatellite instability and both the tumour and normal tissue were PMS2-deficient on IHC (Jackson 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.94		Gain of catalytic residue at S46 (P = 0.0557);Gain of catalytic residue at S46 (P = 0.0557);
MVP		0.96
MPC		0.26
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121434629; hg19: chr7-6045549;