7-5995612-T-C

Variant names:

• chr7-5995612-T-C
• rs876659736
• NM_000535.7:c.825A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000535.7(PMS2):​c.825A>G​(p.Gln275Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -1.29

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5995612-T-C is Pathogenic according to our data. Variant chr7-5995612-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5995612-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.825A>G	p.Gln275Gln	synonymous_variant	Exon 8 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.825A>G	p.Gln275Gln	synonymous_variant	Exon 8 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251422 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460892 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726826

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Pathogenic:4

Sep 19, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2019

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3, PS4_SUP, PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.825A>G pathogenic mutation (also known as p.Q275Q), located in coding exon 8, results from an A to G substitution at nucleotide position 825 of the PMS2 gene. This nucleotide substitution does not change the amino acid at codon 275. In one study, this alteration was detected in trans with a pathogenic PMS2 mutation in a patient diagnosed with rectal adenomatous polyps, cutaneous lentigines, and hyperpigmentation at age 24 whose family history included a sister with a brain tumor at age 11; these findings are consistent with constitutional mismatch repair deficiency (CMMR-D). RNA analysis of this variant showed abnormal splicing leading to premature protein truncation, and absence of PMS2 by immunohistochemistry was noted in the adenoma, brain tumor, and normal tissues from the proband and the affected sister (Johannesma PC et al. Clin. Genet. 2011 Sep;80:243-55). Additionally, a minigene assay of this variant showed out of frame skipping of the first 22 nucleotides of exon 8, and no full length transcript was produced from the variant allele (van der Klift HM et al. Mol Genet Genomic Med 2015 Jul;3:327-45). This alteration was also reported in conjunction with an alteration in MLH1 (p.Y684D) in a patient diagnosed with colon at 35 years old, belonged to an Amsterdam I family, and showed absent staining of MLH1/PMS2 on IHC (Martin-Morales L et al. PLoS ONE, 2018 Sep;13:e0203885). Of note, this alteration has also been reported in a patient with breast cancer diagnosed at age 52 (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jun 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Mar 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.825A>G alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. Publications report experimental evidence that this variant affects mRNA splicing, resulting in a deletion of 22 nt (Johannesma_2011, van der Klift_2015). The variant allele was found at a frequency of 8e-06 in 251422 control chromosomes (gnomAD). c.825A>G has been reported in the literature in the compound heterozygous state with other pathogenic variants in individuals affected with features of constitutional mismatch repair deficiency (e.g. Johannesma_2011, Mishra_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21261604, 26247049, 35532657). ClinVar contains an entry for this variant (Variation ID: 232390). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Sep 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Feb 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30256826, 27435373, 25856668, 28514183, 30787465, 26110232, 30589920, 35477782, 34172528, 36988593, 35532657, 21261604, 26247049) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with Lynch syndrome and symptoms consistent with constitutional mismatch repair deficiency (CMMR-D) (PMID: 21261604, 25856668, 26110232, 28514183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 232390). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	19
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs876659736; hg19: chr7-6035243; COSMIC: COSV99764633;