NM_000535.7(PMS2):c.943C>T (p.Arg315Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 10, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000115711.19

Allele description [Variation Report for NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)]

NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)

Other names:

p.R315*:CGA>TGA

HGVS:

NC_000007.14:g.5992018G>A
NG_008466.1:g.22089C>T
NM_000535.7:c.943C>TMANE SELECT
NM_001322003.2:c.538C>T
NM_001322004.2:c.538C>T
NM_001322005.2:c.538C>T
NM_001322006.2:c.943C>T
NM_001322007.2:c.625C>T
NM_001322008.2:c.625C>T
NM_001322009.2:c.538C>T
NM_001322010.2:c.538C>T
NM_001322011.2:c.10C>T
NM_001322012.2:c.10C>T
NM_001322013.2:c.370C>T
NM_001322014.2:c.943C>T
NM_001322015.2:c.634C>T
NP_000526.2:p.Arg315Ter
NP_001308932.1:p.Arg180Ter
NP_001308933.1:p.Arg180Ter
NP_001308934.1:p.Arg180Ter
NP_001308935.1:p.Arg315Ter
NP_001308936.1:p.Arg209Ter
NP_001308937.1:p.Arg209Ter
NP_001308938.1:p.Arg180Ter
NP_001308939.1:p.Arg180Ter
NP_001308940.1:p.Arg4Ter
NP_001308941.1:p.Arg4Ter
NP_001308942.1:p.Arg124Ter
NP_001308943.1:p.Arg315Ter
NP_001308944.1:p.Arg212Ter
LRG_161t1:c.943C>T
LRG_161:g.22089C>T
NC_000007.13:g.6031649G>A
NM_000535.5:c.943C>T
NM_000535.6:c.943C>T
NR_136154.1:n.1030C>T
p.Arg315Stop
p.R315*

Protein change:

R124*

Links:

dbSNP: rs200640585

Molecular consequence:

NR_136154.1:n.1030C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322003.2:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322004.2:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322005.2:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322006.2:c.943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322007.2:c.625C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322008.2:c.625C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322009.2:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322010.2:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322011.2:c.10C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322012.2:c.10C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322013.2:c.370C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322014.2:c.943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001322015.2:c.634C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212770	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 8, 2025)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 20205264, 22918162, 23709753, 25430799, 25477341, 25856668, 26681312, 27589204, 28724667, 30376427, 30521064, 31056861, 31992580, 32012241, 32885271, 34285288 Citation Link,
SCV000691128	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 10, 2025)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 20205264, 22918162, 23709753, 25856668, 27589204, 30376427, 30521064, 31056861, 31992580, 34285288, 25741868
SCV002530410	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Dec 25, 2020)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 20205264, 22918162, 23709753, 25477341, 27589204, 25856668, 24362816 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212770

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 8, 2025)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link,

SCV000691128

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 10, 2025)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002530410

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Dec 25, 2020)

germline

curation

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Genetic features of Lynch syndrome in the Israeli population.

Goldberg Y, Barnes-Kedar I, Lerer I, Halpern N, Plesser M, Hubert A, Kadouri L, Goldshmidt H, Solar I, Strul H, Rosner G, Baris HN, Peretz T, Levi Z, Kariv R.

Clin Genet. 2015 Jun;87(6):549-53. doi: 10.1111/cge.12530. Epub 2014 Nov 28.

PubMed [citation]

PMID:: 25430799

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21..

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

See all PubMed Citations (18)

Details of each submission

From Ambry Genetics, SCV000212770.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The p.R315* pathogenic mutation (also known as c.943C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 943. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or absent PMS2 by immunohistochemistry (IHC) (Vaughn CP et al. Hum Mutat, 2010 May;31:588-93; Shia J et al. Mod. Pathol., 2013 Jan;26:131-8; Borràs E et al. J Med Genet, 2013 Aug;50:552-63; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Guo X et al. Mol Genet Genomic Med, 2019 06;7:e721; Maynard H et al. Cancer, 2020 01;126:1995-2002; Wang Q et al. J Med Genet, 2020 07;57:487-499; Choi YY et al. Sci Rep, 2021 07;11:14807). Pathogenicity of this mutation has been supported by a functional assay showing reduced mismatch repair activity in vitro and lack of full length PMS2 protein expression (Hinrichsen I et al. Carcinogenesis. 2015 Feb;36:202-11). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000691128.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant changes 1 nucleotide in exon 9 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 individuals affected with Lynch syndrome associated cancers with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 30376427, 30521064, 31056861, 31992580, 34285288). This variant has been identified in 5/282632 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002530410.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 27, 2026

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