NM_000535.7:c.765C>A

Variant names:

• chr7-5997364-G-T
• rs573125799
• NM_000535.7:c.765C>A

Variant summary

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

The NM_000535.7(PMS2):​c.765C>A​(p.Tyr255*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,601,158 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 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: -1.06

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 7-5997364-G-T is Pathogenic according to our data. Variant chr7-5997364-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 183716.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.765C>A	p.Tyr255*	stop_gained	Exon 7 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.765C>A	p.Tyr255*	stop_gained	Exon 7 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150206 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450952 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722706

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: 0.0000562

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150206 Hom.: 0 Cov.: 29 AF XY: 0.0000137 AC XY: 1 AN XY: 73084

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Sep 07, 2017

True Health Diagnostics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 16, 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 7 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, suspected Lynch syndrome, or colorectal cancer with PMS2-negative immunohistochemistry results (PMID: 23012243, 25871621, 25856668, 25980754, 26895986), or endometrial cancer (PMID: 27443514). This variant has been identified in 1/31080 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. -

Nov 13, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.765C>A (p.Y255*) alteration, located in exon 7 (coding exon 7) of the PMS2 gene, consists of a C to A substitution at nucleotide position 765. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 255. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (1/31080) total alleles studied. The highest observed frequency was 0.007% (1/15280) of European (non-Finnish) alleles. This variant has previously been identified in a patient whose sigmoid colon tumor showed microsatellite instability (MSI-H) and isolated absence of PMS2 on immunohistochemistry (IHC) (Dudley, 2015). This variant was also identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Lynch syndrome Pathogenic:3

Sep 27, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PMS2 c.765C>A (p.Tyr255X) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.823C>T (p.Gln275X), c.861_864delACAG (p.Arg287fsX19), c.1021delA (p.Arg341fsX15)). The variant has been reported in multiple patients with colorectal cancer and other LS-associated tumors from Lynch syndrome families (e.g. Rosty_2016, Yurgelun_2015, Dudley_2015). This variant was found in 1/30666 control chromosomes at a frequency of 0.0000326, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Nov 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr255X variant in PMS2 has been reported in at least 3 individuals with PMS2-associated cancers (Dudley 2015 PMID: 25871621, Yurgelun 2015 PMID: 25980754, Goodenberger 2016 PMID: 25856668). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183716) and was identified in 0.007% (1/15280) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 255, which is predicted to lead to a truncated or absent protein. Heterozygous 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_Supporting, PS4_Supporting. -

Aug 01, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 7 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, suspected Lynch syndrome, or colorectal cancer with PMS2-negative immunohistochemistry results (PMID: 23012243, 25871621, 25856668, 25980754, 26895986), or endometrial cancer (PMID: 27443514). This variant has been identified in 1/31080 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. -

not provided Pathogenic:3

Dec 22, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of PMS2 protein synthesis. It has been reported in individuals with colorectal and endometrial cancer in the published literature (PMID: 26895986 (2016), 27443514 (2016), 25856668 (2015), 25871621 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -

May 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 multiple individuals with a personal and/or family history of PMS2-related cancers (Vaughn et al., 2013; Dudley et al., 2015; Goodenberger et al., 2016; Ring et al., 2016; Rosty et al., 2016; Yurgelun et al., 2017); 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: 29478780, 27882345, 26895986, 23012243, 29345684, 28888541, 31447099, 25980754, 25871621, 25856668, 28135145, 27443514, 29596542, 32719484, 30787465) -

Lynch syndrome 4 Pathogenic:3

Sep 19, 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 16, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.765C>A (p.Tyr255Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Lynch-syndrome associated cancers (PMID: 25871621, 27443514, 28888541, 35346574). This variant has also been reported in the compound heterozygous state with another pathogenic PMS2 variant in an individual with constitutional mismatch repair deficiency (internal data). This variant has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Mar 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.765C>A variant is predicted to result in premature protein termination (p.Tyr255*). This variant has been reported in multiple individuals with personal or family histories consistent with Lynch syndrome (Vaughn et al. 2013. PubMed ID: 23012243, Table S1; Dudley et al. 2015. PubMed ID: 25871621, Table 1; Yurgelun et al. 2015. PubMed ID: 25980754, Table S1; Goodenberger et al. 2016. PubMed ID: 25856668, Table S1; Ring et al. 2016. PubMed ID: 27443514; Rosty et al. 2016. PubMed ID: 26895986, Table S2). This variant is reported in 0.0065% of alleles in individuals of European (non-Finnish) descent in gnomAD and it is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183716/). Nonsense variants in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 04, 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.Tyr255*) 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 (rs573125799, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colorectal cancer (PMID: 23012243, 25856668, 25871621, 25980754). 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: 183716). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.16	N
Vest4		0.87
GERP RS		-9.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs573125799; hg19: chr7-6036995;