NM_000179.3(MSH6):c.2291C>A (p.Thr764Asn) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 10, 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:: RCV002307420.1

Allele description [Variation Report for NM_000179.3(MSH6):c.2291C>A (p.Thr764Asn)]

NM_000179.3(MSH6):c.2291C>A (p.Thr764Asn)

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.2291C>A (p.Thr764Asn)

HGVS:

NC_000002.12:g.47800274C>A
NG_007111.1:g.22128C>A
NM_000179.3:c.2291C>AMANE SELECT
NM_001281492.2:c.1901C>A
NM_001281493.2:c.1385C>A
NM_001281494.2:c.1385C>A
NP_000170.1:p.Thr764Asn
NP_000170.1:p.Thr764Asn
NP_001268421.1:p.Thr634Asn
NP_001268422.1:p.Thr462Asn
NP_001268423.1:p.Thr462Asn
LRG_219t1:c.2291C>A
LRG_219:g.22128C>A
LRG_219p1:p.Thr764Asn
NC_000002.11:g.48027413C>A
NM_000179.2:c.2291C>A
p.T764N

Protein change:

T462N

Links:

dbSNP: rs561198849

NCBI 1000 Genomes Browser:

rs561198849

Molecular consequence:

NM_000179.3:c.2291C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1901C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1385C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1385C>A - 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
SCV002600391	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 10, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15713769, 32547938 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002600391

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 10, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Nikitin AG, Chudakova DA, Enikeev RF, Sakaeva D, Druzhkov M, Shigapova LH, Brovkina OI, Shagimardanova EI, Gusev OA, Gordiev MG.

Front Oncol. 2020;10:666. doi: 10.3389/fonc.2020.00666.

PubMed [citation]

PMID:: 32547938
PMCID:: PMC7273971

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600391.1

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

Description

Variant summary: MSH6 c.2291C>A (p.Thr764Asn) results in a non-conservative amino acid change DNA mismatch repair protein MutS core (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2291C>A has been reported in the literature in individuals affected with Colorectal cancer and Breast cancer without stong evidence for causality (Casey_2005, Nikitin_2020). These data do not allow any conclusion about variant significance. Co-occurrence with another pathogenic variant have been reported (MLH1 c.350C>G, p.Thr117Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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: May 7, 2024

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