NM_000179.3(MSH6):c.2624T>C (p.Met875Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002271437.1

Allele description [Variation Report for NM_000179.3(MSH6):c.2624T>C (p.Met875Thr)]

NM_000179.3(MSH6):c.2624T>C (p.Met875Thr)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.2624T>C (p.Met875Thr)

HGVS:

NC_000002.12:g.47800607T>C
NG_007111.1:g.22461T>C
NM_000179.3:c.2624T>CMANE SELECT
NM_001281492.2:c.2234T>C
NM_001281493.2:c.1718T>C
NM_001281494.2:c.1718T>C
NP_000170.1:p.Met875Thr
NP_000170.1:p.Met875Thr
NP_001268421.1:p.Met745Thr
NP_001268422.1:p.Met573Thr
NP_001268423.1:p.Met573Thr
LRG_219t1:c.2624T>C
LRG_219:g.22461T>C
LRG_219p1:p.Met875Thr
NC_000002.11:g.48027746T>C
NM_000179.2:c.2624T>C
p.M875T

Protein change:

M573T

Links:

dbSNP: rs774774596

NCBI 1000 Genomes Browser:

rs774774596

Molecular consequence:

NM_000179.3:c.2624T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2234T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1718T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1718T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002556001	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002556001

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 20, 2022)

germline

clinical testing

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

Citation Link

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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002556001.1

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

Description

Variant summary: MSH6 c.2624T>C (p.Met875Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2624T>C has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with a diagnosis of core binding factor AML in a cohort of individuals with pediatric cancers (example, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 13, 2024

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