NM_000535.7(PMS2):c.1186A>G (p.Met396Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 15, 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:: RCV000220813.8

Allele description [Variation Report for NM_000535.7(PMS2):c.1186A>G (p.Met396Val)]

NM_000535.7(PMS2):c.1186A>G (p.Met396Val)

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.1186A>G (p.Met396Val)

HGVS:

NC_000007.14:g.5987579T>C
NG_008466.1:g.26528A>G
NM_000535.7:c.1186A>GMANE SELECT
NM_001322003.2:c.781A>G
NM_001322004.2:c.781A>G
NM_001322005.2:c.781A>G
NM_001322006.2:c.1030A>G
NM_001322007.2:c.868A>G
NM_001322008.2:c.868A>G
NM_001322009.2:c.781A>G
NM_001322010.2:c.625A>G
NM_001322011.2:c.253A>G
NM_001322012.2:c.253A>G
NM_001322013.2:c.613A>G
NM_001322014.2:c.1186A>G
NM_001322015.2:c.877A>G
NP_000526.2:p.Met396Val
NP_001308932.1:p.Met261Val
NP_001308933.1:p.Met261Val
NP_001308934.1:p.Met261Val
NP_001308935.1:p.Met344Val
NP_001308936.1:p.Met290Val
NP_001308937.1:p.Met290Val
NP_001308938.1:p.Met261Val
NP_001308939.1:p.Met209Val
NP_001308940.1:p.Met85Val
NP_001308941.1:p.Met85Val
NP_001308942.1:p.Met205Val
NP_001308943.1:p.Met396Val
NP_001308944.1:p.Met293Val
LRG_161t1:c.1186A>G
LRG_161:g.26528A>G
NC_000007.13:g.6027210T>C
NM_000535.5:c.1186A>G
NM_000535.6:c.1186A>G
NR_136154.1:n.1273A>G

Protein change:

M205V

Links:

dbSNP: rs863224675

NCBI 1000 Genomes Browser:

rs863224675

Molecular consequence:

NM_000535.7:c.1186A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.781A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.781A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.781A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1030A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.868A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.868A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.781A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.625A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.253A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.253A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.613A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1186A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.877A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1273A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; 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
SCV000273471	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jun 15, 2023)	germline	clinical testing	Citation Link,
SCV001353139	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273471

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jun 15, 2023)

germline

clinical testing

Citation Link,

SCV001353139

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 21, 2021)

germline

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000273471.7

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

Description

The p.M396V variant (also known as c.1186A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1186. The methionine at codon 396 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001353139.2

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

Description

This missense variant replaces methionine with valine at codon 396 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31394 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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