rs63750490

Positions:

• chr7-5986925-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000265849.12(PMS2):​c.1840A>T​(p.Lys614Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000752 in 1,461,880 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K614K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PMS2 ENST00000265849.12 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 5.40

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-5986925-T-A is Pathogenic according to our data. Variant chr7-5986925-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 91318.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986925-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1840A>T	p.Lys614Ter	stop_gained	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1840A>T	p.Lys614Ter	stop_gained	11/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000935 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Lys614X variant in PMS2 has been reported in 4 heterozygous individuals with colon cancer and 2 homozygous individuals with colorectal cancer ad astrocytomas (Yurgelun 2015, Herkert 2011, Senter 2008, Gururangan 2008). It segregated with PMS2-related cancer in one relative (Gururangan 2008). This variant was absent from large population studies and was classified as pathogenic on September 5, 2013 by the ClinGen-approved inSIGHT expert panel (ClinVar ID 91318). This nonsense variant leads to a premature termination codon at position 614, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). Tumor data from affected individuals has demonstrated loss of PMS2 protein via immunohistochemistry or high microsatellite instability (PMID: 17993636, 18809606). This variant has not been identified 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. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	nonsense/frameshift -
Pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Aug 01, 2017	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 66 year old female with a personal history of uterine cancer and family history of colorectal cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 18809606, 18602922, 25980754); Observed homozygous in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 17993636); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25980754, 21376568, 25856668, 14574005, 22577899, 18809606, 25691505, 18602922, 31447099, 30787465, 33087929, 28888541, 36922933, 17993636) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 28, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Lys614* variant was identified in 2 of 198 proband chromosomes (frequency: 0.01) from individuals or families with colorectal cancer (Senter 2008). The variant was also identified in 3 probands of consanguineous parents with constitutional mismatch repair deficiency syndrome (Baas 2013, Gururangan 2007). The variant was also identified in dbSNP (ID: rs63750490) as "With Pathogenic allele ", ClinVar (classified as Pathogenic by Invitae, Ambry Genetics, GeneDx, InSight and Color), Cosmic (1x in large intestine tissue), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (4x), databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Lys614* variant leads to a premature stop codon at position 614, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in PMS2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2021	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). This variant has not been identified 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2022	The p.K614* pathogenic mutation (also known as c.1840A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1840. This changes the amino acid from a lysine to a stop codon within coding exon 11. This mutation has been detected in colorectal and endometrial cancer patients whose tumors demonstrated isolated absence of PMS2 by immunohistochemistry (Senter L et al. Gastroenterology 2008 Aug;135(2):419-28). It has also been identified in a homozygous state in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome, including colorectal cancer and high grade astrocytoma before age 20y (Gururangan S et al. Neuro-oncology 2008 Feb;10(1):93-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 21, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 06, 2018	The c.1840A>T (p.Lys614*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome related tumors (PMID 17993636, 18602922,25980754) or constitutional mismatch repair deficiency syndrome (PMID 17993636). Therefore, this c.1840A>T (p.Lys614*) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 13, 2022	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 09, 2020

Variant summary: PMS2 c.1840A>T (p.Lys614X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251450 control chromosomes. c.1840A>T has been reported in the literature in the heterozygous state in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and/or endometrial cancer (e.g. Senter_2008, Gururangan_2008, Yurgelun_2015). The variant has also been reported in the homozygous state in at least one individual affected by constitutional mismatch repair syndrome (e.g. Gururangan_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change creates a premature translational stop signal (p.Lys614*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and colorectal cancer and/or endometrial cancer (PMID: 17993636, 18602922, 21376568, 22577899, 22692065, 25856668). ClinVar contains an entry for this variant (Variation ID: 91318). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;D;D
Vest4		0.92
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs63750490; hg19: chr7-6026556; COSMIC: COSV56221044;