NM_000179.3(MSH6):c.980C>G (p.Thr327Ser) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 27, 2023
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:: RCV003995316.2

Allele description [Variation Report for NM_000179.3(MSH6):c.980C>G (p.Thr327Ser)]

NM_000179.3(MSH6):c.980C>G (p.Thr327Ser)

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.980C>G (p.Thr327Ser)

HGVS:

NC_000002.12:g.47798963C>G
NG_007111.1:g.20817C>G
NM_000179.3:c.980C>GMANE SELECT
NM_001281492.2:c.590C>G
NM_001281493.2:c.74C>G
NM_001281494.2:c.74C>G
NP_000170.1:p.Thr327Ser
NP_000170.1:p.Thr327Ser
NP_001268421.1:p.Thr197Ser
NP_001268422.1:p.Thr25Ser
NP_001268423.1:p.Thr25Ser
LRG_219t1:c.980C>G
LRG_219:g.20817C>G
LRG_219p1:p.Thr327Ser
NC_000002.11:g.48026102C>G
NM_000179.2:c.980C>G
p.T327S

Protein change:

T197S

Links:

dbSNP: rs369568820

NCBI 1000 Genomes Browser:

rs369568820

Molecular consequence:

NM_000179.3:c.980C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.590C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.74C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.74C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004837525	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23047549, 25479140, 31391288, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004837525

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 27, 2023)

germline

clinical testing

PubMed (5)
[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	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23047549
PMCID:: PMC3493867

Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.

Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S.

Gastroenterology. 2015 Mar;148(3):556-64. doi: 10.1053/j.gastro.2014.11.042. Epub 2014 Dec 2.

PubMed [citation]

PMID:: 25479140
PMCID:: PMC4339623

See all PubMed Citations (5)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004837525.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces threonine with serine at codon 327 of the MSH6 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 performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140), and unspecified cancer (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 6/282796 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	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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