NM_000535.7(PMS2):c.943C>T (p.Arg315Ter) AND Lynch syndrome 4

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 2, 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:: RCV000576503.10

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]

Observations:

Condition(s)

Name:: Lynch syndrome 4 (LYNCH4)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 4; Hereditary non-polyposis colorectal cancer, type 4
Identifiers:: MONDO: MONDO:0013699; MedGen: C1838333; Orphanet: 144; OMIM: 614337

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000677745	Counsyl	no assertion criteria provided	Pathogenic (Oct 2, 2015)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23709753, 25525159, 25477341, 25637381, 20205264
SCV004019893	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 5, 2023)	unknown	clinical testing	Citation Link,
SCV004205420	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005044161	New York Genome Center - PrenatalSEQ	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Nov 15, 2022)	inherited	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20205264, 22918162, 23709753, 25856668, 27589204, 31297337, 3199258 Citation Link,
SCV006324910	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	pathogenic (Jul 2, 2025)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

Functional testing strategy for coding genetic variants of unclear significance in MLH1 in Lynch syndrome diagnosis.

Hinrichsen I, Schäfer D, Langer D, Köger N, Wittmann M, Aretz S, Steinke V, Holzapfel S, Trojan J, König R, Zeuzem S, Brieger A, Plotz G.

Carcinogenesis. 2015 Feb;36(2):202-11. doi: 10.1093/carcin/bgu239. Epub 2014 Dec 4.

PubMed [citation]

PMID:: 25477341

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000677745.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

From Myriad Genetics, Inc., SCV004019893.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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

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

From Baylor Genetics, SCV004205420.1

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

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

From New York Genome Center - PrenatalSEQ, SCV005044161.1

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

Description

The c.943C>T variant in PMS2 has previously been reported in individuals or families with lynch syndrome and colon cancer [PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 31297337, 31992580]. This variant was also identified in an asymptomatic carrier from a Lynch syndrome family [PMID: 23709753] and it has been deposited in ClinVar [ClinVar ID: 91382] as Pathogenic. The c.943C>T variant is observed in 14 alleles (~0.0017% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.943C>T variant in PMS2 is located in exon 9 of this 15-exon gene, predicted to incorporate a premature termination codon p.(Arg315Ter), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.943C>T variant have been reported in the literature [PMID: 31992580] and ClinVar [ClinVar ID: 91299] in individuals with Lynch syndrome. In vitro functional studies demonstrated reduced mismatch repair activity and lack of full length PMS2 protein expression in human embryonic kidney cells (HEK293T) carrying c.943C>T variant [PMID: 25477341]. Based on available evidence this inherited c.943C>T p.(Arg315Ter) variant identified in PMS2 is classified here as Pathogenic.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV006324910.1

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

Description

Criteria applied: PVS1,PP4_SUP,PM2_SUP

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

Last Updated: Jul 27, 2026

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