NM_000535.7(PMS2):c.2367G>A (p.Met789Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 8, 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:: RCV000561492.6

Allele description [Variation Report for NM_000535.7(PMS2):c.2367G>A (p.Met789Ile)]

NM_000535.7(PMS2):c.2367G>A (p.Met789Ile)

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.2367G>A (p.Met789Ile)

HGVS:

NC_000007.14:g.5977666C>T
NG_008466.1:g.36441G>A
NM_000535.7:c.2367G>AMANE SELECT
NM_001322003.2:c.1962G>A
NM_001322004.2:c.1962G>A
NM_001322005.2:c.1962G>A
NM_001322006.2:c.2211G>A
NM_001322007.2:c.2049G>A
NM_001322008.2:c.2049G>A
NM_001322009.2:c.1995G>A
NM_001322010.2:c.1806G>A
NM_001322011.2:c.1434G>A
NM_001322012.2:c.1434G>A
NM_001322013.2:c.1794G>A
NM_001322014.2:c.2400G>A
NM_001322015.2:c.2058G>A
NP_000526.2:p.Met789Ile
NP_001308932.1:p.Met654Ile
NP_001308933.1:p.Met654Ile
NP_001308934.1:p.Met654Ile
NP_001308935.1:p.Met737Ile
NP_001308936.1:p.Met683Ile
NP_001308937.1:p.Met683Ile
NP_001308938.1:p.Met665Ile
NP_001308939.1:p.Met602Ile
NP_001308940.1:p.Met478Ile
NP_001308941.1:p.Met478Ile
NP_001308942.1:p.Met598Ile
NP_001308943.1:p.Met800Ile
NP_001308944.1:p.Met686Ile
LRG_161t1:c.2367G>A
LRG_161:g.36441G>A
NC_000007.13:g.6017297C>T
NM_000535.5:c.2367G>A
NM_000535.6:c.2367G>A
NR_136154.1:n.2411G>A

Protein change:

M478I

Links:

dbSNP: rs766565506

NCBI 1000 Genomes Browser:

rs766565506

Molecular consequence:

NM_000535.7:c.2367G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1962G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1962G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1962G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.2211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.2049G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.2049G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1995G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1806G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1794G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2400G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.2058G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2411G>A - 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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SRP219299 (6)
SRA
ND4 [Onychostoma lini]
ND4 [Onychostoma lini]
Gene ID:13080268

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000663503	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004359001	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31391288, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000663503

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 8, 2024)

germline

clinical testing

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

Citation Link,

SCV004359001

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 21, 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

Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV.

Hum Mutat. 2013 Jan;34(1):255-65. doi: 10.1002/humu.22214. Epub 2012 Oct 22.

PubMed [citation]

PMID:: 22949387
PMCID:: PMC4318556

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

Li S, Qian D, Thompson BA, Gutierrez S, Wu S, Pesaran T, LaDuca H, Lu HM, Chao EC, Black MH.

J Med Genet. 2020 Jan;57(1):62-69. doi: 10.1136/jmedgenet-2019-106096. Epub 2019 Aug 7.

PubMed [citation]

PMID:: 31391288

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000663503.7

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

Description

The p.M789I variant (also known as c.2367G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2367. The methionine at codon 789 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant 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, SCV004359001.1

#	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 isoleucine at codon 789 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with unspecified cancer (PMID: 31391288). This variant has not been identified 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: Oct 8, 2024

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