Submissions for variant NM_000535.7(PMS2):c.765C>A (p.Tyr255Ter)

dbSNP: rs573125799

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162412	SCV000212750	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-05	criteria provided, single submitter	clinical testing	The p.Y255* pathogenic mutation (also known as c.765C>A), located in coding exon 7 of the PMS2 gene, results from a C to A substitution at nucleotide position 765. This changes the amino acid from a tyrosine to a stop codon within coding exon 7. This mutation 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 B et al. Am. J. Surg. Pathol. 2015 Aug;39:1114-20). This alteration 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 MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). 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.
Invitae	RCV000627717	SCV000219144	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	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). 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 (Invitae). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168447	SCV000271441	pathogenic	Lynch syndrome	2022-11-23	criteria provided, single submitter	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.
GeneDx	RCV000413496	SCV000490729	pathogenic	not provided	2023-05-04	criteria provided, single submitter	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)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413496	SCV000601860	pathogenic	not provided	2021-05-21	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000162412	SCV000911689	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168447	SCV000920038	pathogenic	Lynch syndrome	2017-09-27	criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV000413496	SCV002018875	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162412	SCV002530383	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-13	criteria provided, single submitter	curation
Baylor Genetics	RCV003147375	SCV003836192	pathogenic	Lynch syndrome 4	2022-03-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407601	SCV004108688	pathogenic	PMS2-related disorder	2023-08-04	criteria provided, single submitter	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 (http://gnomad.broadinstitute.org/variant/7-6036995-G-T) and 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003147375	SCV004171478	pathogenic	Lynch syndrome 4	2023-10-16	criteria provided, single submitter	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.
Myriad Genetics, Inc.	RCV003147375	SCV004187722	pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV000168447	SCV004839918	pathogenic	Lynch syndrome	2023-12-13	criteria provided, single submitter	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.
True Health Diagnostics	RCV000162412	SCV000788119	pathogenic	Hereditary cancer-predisposing syndrome	2017-09-07	no assertion criteria provided	clinical testing