NM_000535.7(PMS2):c.934A>G (p.Met312Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 24, 2024
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:: RCV000165431.11

Allele description [Variation Report for NM_000535.7(PMS2):c.934A>G (p.Met312Val)]

NM_000535.7(PMS2):c.934A>G (p.Met312Val)

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.934A>G (p.Met312Val)

HGVS:

NC_000007.14:g.5992027T>C
NG_008466.1:g.22080A>G
NM_000535.7:c.934A>GMANE SELECT
NM_001322003.2:c.529A>G
NM_001322004.2:c.529A>G
NM_001322005.2:c.529A>G
NM_001322006.2:c.934A>G
NM_001322007.2:c.616A>G
NM_001322008.2:c.616A>G
NM_001322009.2:c.529A>G
NM_001322010.2:c.529A>G
NM_001322011.2:c.1A>G
NM_001322012.2:c.1A>G
NM_001322013.2:c.361A>G
NM_001322014.2:c.934A>G
NM_001322015.2:c.625A>G
NP_000526.2:p.Met312Val
NP_001308932.1:p.Met177Val
NP_001308933.1:p.Met177Val
NP_001308934.1:p.Met177Val
NP_001308935.1:p.Met312Val
NP_001308936.1:p.Met206Val
NP_001308937.1:p.Met206Val
NP_001308938.1:p.Met177Val
NP_001308939.1:p.Met177Val
NP_001308940.1:p.Met1Val
NP_001308941.1:p.Met1Val
NP_001308942.1:p.Met121Val
NP_001308943.1:p.Met312Val
NP_001308944.1:p.Met209Val
LRG_161t1:c.934A>G
LRG_161:g.22080A>G
NC_000007.13:g.6031658T>C
NM_000535.5:c.934A>G
NM_000535.6:c.934A>G
NR_136154.1:n.1021A>G
p.M312V

Protein change:

M121V

Links:

dbSNP: rs786202567

NCBI 1000 Genomes Browser:

rs786202567

Molecular consequence:

NM_001322011.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322012.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000535.7:c.934A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.934A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.616A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.616A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.934A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.625A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1021A>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
SCV000216160	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 24, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001360180	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31942411, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216160

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 24, 2024)

germline

clinical testing

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

Citation Link,

SCV001360180

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 8, 2022)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular Basis of Inherited Colorectal Carcinomas in the Macedonian Population: An Update.

Staninova-Stojovska M, Matevska-Geskovska N, Panovski M, Angelovska B, Mitrevski N, Ristevski M, Jovanovic R, Dimovski AJ.

Balkan J Med Genet. 2019 Dec;22(2):5-16. doi: 10.2478/bjmg-2019-0027.

PubMed [citation]

PMID:: 31942411
PMCID:: PMC6956642

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, SCV000216160.9

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

Description

The p.M312V variant (also known as c.934A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide position 934. The methionine at codon 312 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in 1/107 Macedonian individuals with a clinical history of hereditary polyposis or hereditary non-polyposis colorectal cancer who underwent multi-gene panel testing. (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). This amino acid position is not well conserved in available 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, SCV001360180.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces methionine with valine at codon 312 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hereditary non-polyposis colorectal cancer (PMID: 31942411) and in an individual affected with prostate cancer (Color internal data). This variant has been identified in 1/251298 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: Sep 29, 2024

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