NM_000535.7(PMS2):c.944G>A (p.Arg315Gln) AND Lynch syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 13, 2023
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:: RCV000197131.12

Allele description [Variation Report for NM_000535.7(PMS2):c.944G>A (p.Arg315Gln)]

NM_000535.7(PMS2):c.944G>A (p.Arg315Gln)

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.944G>A (p.Arg315Gln)

HGVS:

NC_000007.14:g.5992017C>T
NG_008466.1:g.22090G>A
NM_000535.7:c.944G>AMANE SELECT
NM_001322003.2:c.539G>A
NM_001322004.2:c.539G>A
NM_001322005.2:c.539G>A
NM_001322006.2:c.944G>A
NM_001322007.2:c.626G>A
NM_001322008.2:c.626G>A
NM_001322009.2:c.539G>A
NM_001322010.2:c.539G>A
NM_001322011.2:c.11G>A
NM_001322012.2:c.11G>A
NM_001322013.2:c.371G>A
NM_001322014.2:c.944G>A
NM_001322015.2:c.635G>A
NP_000526.2:p.Arg315Gln
NP_001308932.1:p.Arg180Gln
NP_001308933.1:p.Arg180Gln
NP_001308934.1:p.Arg180Gln
NP_001308935.1:p.Arg315Gln
NP_001308936.1:p.Arg209Gln
NP_001308937.1:p.Arg209Gln
NP_001308938.1:p.Arg180Gln
NP_001308939.1:p.Arg180Gln
NP_001308940.1:p.Arg4Gln
NP_001308941.1:p.Arg4Gln
NP_001308942.1:p.Arg124Gln
NP_001308943.1:p.Arg315Gln
NP_001308944.1:p.Arg212Gln
LRG_161t1:c.944G>A
LRG_161:g.22090G>A
NC_000007.13:g.6031648C>T
NM_000535.5:c.944G>A
NM_000535.6:c.944G>A
NR_136154.1:n.1031G>A
p.R315Q

Protein change:

R124Q

Links:

dbSNP: rs116314131

NCBI 1000 Genomes Browser:

rs116314131

Molecular consequence:

NM_000535.7:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.11G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.11G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.371G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.635G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1031G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266222	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Uncertain significance (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000700120	CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Uncertain significance (Oct 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004839875	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25503501, 26845104, 27498913, 32980694, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000266222

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts et al. (Genet Med 2016))

Uncertain significance
(Nov 20, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000700120

CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation

criteria provided, single submitter

(Amendola et al. (Genome Res. 2015))

Uncertain significance
(Oct 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004839875

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	no	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	6	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.

Maxwell KN, Wubbenhorst B, D'Andrea K, Garman B, Long JM, Powers J, Rathbun K, Stopfer JE, Zhu J, Bradbury AR, Simon MS, DeMichele A, Domchek SM, Nathanson KL.

Genet Med. 2015 Aug;17(8):630-8. doi: 10.1038/gim.2014.176. Epub 2014 Dec 11.

PubMed [citation]

PMID:: 25503501
PMCID:: PMC4465412

See all PubMed Citations (6)

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	no	1	not provided	not provided		1	not provided	not provided	not provided

From CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation, SCV000700120.1

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

Description

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 66 year old female with uterine cancer diagnosed at age 56 and a family history of colon cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

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

From All of Us Research Program, National Institutes of Health, SCV004839875.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with glutamine at codon 315 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sarcoma (PMID: 27498913), an individual affected with uterine cancer with a family history of ovarian cancer (ClinVar RCV000197131.6), and a third individual affected with early-onset breast cancer who also has a pathogenic CHEK2 mutation (PMID: 25503501). This variant also has been reported in an unaffected individual with a family history of ovarian cancer (PMID: 26845104) and in a pancreatic case-control study where it was detected in several unaffected individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 5/251260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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