rs63751422

Positions:

• chr7-5986838-G-A
• chr7-5986838-G-C

Variant summary

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

The NM_000535.7(PMS2):​c.1927C>T​(p.Gln643Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,512 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 2.65

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 7-5986838-G-A is Pathogenic according to our data. Variant chr7-5986838-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91320.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986838-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1927C>T	p.Gln643Ter	stop_gained	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1927C>T	p.Gln643Ter	stop_gained	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135792

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461470 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727014

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74256

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2021	The p.Gln643X variant in PMS2 has been reported in at least 5 individuals with Lynch syndrome-associated cancers where most tumors lacked PMS2 expression on immunohistochemistry (Senter 2008 PMID: 18602922, Rosty 2016 PMID: 26895986, Okkels 2019 PMID: 31433215, Wang 2020 PMID: 31992580), and segregated with colorectal cancer in 1 affected relative (Agostini 2005 PMID: 16144131). It has also been reported in the compound heterozygous state in 2 individuals with early-onset cancers consistent with Turcot syndrome and in 2 individuals with clinical features of constitutional mismatch repair deficiency (CMMRD; Agostini 2005 PMID: 16144131, Vaughn 2010 PMID: 20205264, Grobner 2018 PMID: 29489754, Rusch 2018 PMID: 30262806). Additionally, this variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 643, 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 as well as autosomal recessive CMMRD. This variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91320). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting) and autosomal recessive CMMRD (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 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 heterozygous carriers affected with colorectal cancer (PMID: 18602922, 26895986, 27273229, 31433215), as well as compound heterozygous carriers with phenotypes consistent with Turcot syndrome and constitutional mismatch repair deficiency syndrome (PMID: 16144131, 20205264). This variant has also been reported in an individual with breast cancer (PMID: 33753322). This variant has been identified in 1/251242 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. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	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; Reported in multiple individuals with colorectal cancer whose tumors lacked PMS2 expression on immunohistochemistry (Senter 2008, Goodenberger 2016, Rosty 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) in patients with constitutional mismatch repair deficiency syndrome in published literature (Agostini 2005, Vaughn 2010); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 26895986, 22658618, 28514183, 29489754, 25637381, 16740762, 21239990, 16144131, 18602922, 18709565, 25856668, 20205264, 21376568, 19283792, 20531397, 16283678, 30262806, 31447099, 31992580, 32231684, 31433215, 32719484, 30755392) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 14, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	The p.Q643* pathogenic mutation (also known as c.1927C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1927. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been reported in multiple individuals with biallelic PMS2 mutations who presented with very early-onset brain tumors, small bowel cancers, and adenomas, whose tumors were microsatellite high and showed isolated loss of PMS2 protein expression (Agostini M et al. Am. J. Gastroenterol. 2005 Aug;100:1886-91; Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Pastrello C et al. Genet. Med. 2011 Feb;13:115-24). This mutation has also been reported in multiple individuals with apparently sporadic colon cancer that showed isolated absence of the PMS2 protein on immunohistochemistry (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). Of note, this mutation is also designated as c.1951C>T in published literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	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 heterozygous carriers affected with colorectal cancer (PMID: 18602922, 26895986, 27273229, 31433215), as well as compound heterozygous carriers with phenotypes consistent with Turcot syndrome and constitutional mismatch repair deficiency syndrome (PMID: 16144131, 20205264). This variant has also been reported in an individual with breast cancer (PMID: 33753322). This variant has been identified in 1/251242 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 Pathogenic:2

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	Baylor Genetics	Mar 27, 2024	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 06, 2023

Variant summary: PMS2 c.1927C>T (p.Gln643X) 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. The variant allele was found at a frequency of 4e-06 in 251280 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1927C>T, has been reported in the literature in numerous individuals affected with Lynch Syndrome (e.g., Senter_2008, Agostini_2005, Rosty_2016). The variant of interest has also been identified in compound heterozygous patients who have early-onset cancers, as well as in heterozygous colorectal cancer patients with a later age of onset than in compound heterozygotes (e.g., Pastrello_2011, Vaughn_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports a loss of PMS2 immunohistochemistry reactivity, suggesting that the transcript undergoes nonsense-mediated decay or the truncated protein product is unstable (e.g., Vaughn_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20205264, 21239990, 16283678, 22658618, 18602922, 16144131, 19283792, 26895986). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Pulmonary valve insufficiency;C0035229:Respiratory insufficiency;C2973725:Pulmonary arterial hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change creates a premature translational stop signal (p.Gln643*) 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 Lynch syndrome, and constitutional mismatch repair deficiency syndrome (PMID: 6144131, 18602922, 20205264, 23012243, 26895986). ClinVar contains an entry for this variant (Variation ID: 91320). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.30	N
MutationTaster	Benign	1.0	A;A;A;N;N
Vest4		0.66
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: rs63751422; hg19: chr7-6026469;