rs63750451

Variant names:

• chr7-5986883-G-A
• rs63750451
• NM_000535.7:c.1882C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5986883-G-A
• chr7-5986883-G-C
• chr7-5986883-G-T

Variant summary

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

The NM_000535.7(PMS2):​c.1882C>T​(p.Arg628*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,858 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 1.60

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 7-5986883-G-A is Pathogenic according to our data. Variant chr7-5986883-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9242.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986883-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1882C>T	p.Arg628*	stop_gained	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1882C>T	p.Arg628*	stop_gained	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251434 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Mar 03, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 27589204 (2016), 27435373 (2016), 16472587 (2006)), breast cancer (PMID: 29345684 (2018)), ovarian/endometrial cancer (PMIDs: 29625052 (2018), 28888541 (2017)), and CMMRD (PMID: 27435373 (2016)). RNA analysis indicated the variant mRNA transcript is subjected to nonsense-mediated decay (PMID: 20186688 (2010)). The frequency of this variant in the general population, 0.000016 (4/251434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with PMS2-related cancers, including those with tumor studies consistent with pathogenic variants in this gene (Hendriks et al., 2006; van Puijenbroek et al., 2008; ten Broeke et al., 2015; Suerink et al., 2016; Sugano et al., 2016); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 20186688, 26110232, 30217226, 28888541, 29758216, 34697415, 25512458, 16472587, 18415027, 25691505, 27589204, 27435373, 28600700, 19283792, 25525159, 30787465, 29625052) -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4 Pathogenic:5

Mar 16, 2016

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Oct 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Aug 06, 2020

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been reported in multiple individuals affected with colorectal or endometrial cancer that exhibited microsatellite instability and loss of PMS2 proteins by immunohistochemistry analyses (PMID: 16472587, 18415027, 27589204, 34253388, 36931573). This variant has also been reported in individuals affected with breast cancer (PMID: 16472587, 29345684). This variant has been identified in 4/251434 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. -

Jan 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R628* pathogenic mutation (also known as c.1882C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1882. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in several unrelated hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients and families; several with tumors demonstrating loss of PMS2 by immunohistochemistry (IHC) (Hendriks YM et al. Gastroenterology, 2006 Feb;130:312-22; van der Klift HM et al. Hum Mutat, 2010 May;31:578-87; Suerink M et al. Genet Med, 2016 Apr;18:405-9; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Post CCB et al. J Natl Cancer Inst, 2021 Sep;113:1212-1220). This mutation has also been identified in two individuals with breast cancer undergoing multi-gene panel testing (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174). 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Jun 24, 2019

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.1882C>T (p.Arg628X) 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. RT-PCR analysis on RNA derived from cultured lymphocytes of patients carrying the variant demonstrated nonsense-mediated RNA decay (van der Klift_2010, 2016). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes (gnomAD). c.1882C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Hendriks_2006, Sugano_2016, van der Klift_2010, 2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg628*) 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 present in population databases (rs63750451, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16472587, 19283792, 25512458, 26110232, 27435373, 27589204). 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: 9242). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.24	N
Vest4		0.88
GERP RS		4.9

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: rs63750451; hg19: chr7-6026514;