NM_000179.3(MSH6):c.926C>G (p.Ser309Cys) AND MSH6-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 31, 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:: RCV004529928.1

Allele description [Variation Report for NM_000179.3(MSH6):c.926C>G (p.Ser309Cys)]

NM_000179.3(MSH6):c.926C>G (p.Ser309Cys)

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.926C>G (p.Ser309Cys)

Other names:

p.S309C:TCT>TGT

HGVS:

NC_000002.12:g.47798909C>G
NG_007111.1:g.20763C>G
NM_000179.3:c.926C>GMANE SELECT
NM_001281492.2:c.536C>G
NM_001281493.2:c.20C>G
NM_001281494.2:c.20C>G
NP_000170.1:p.Ser309Cys
NP_000170.1:p.Ser309Cys
NP_001268421.1:p.Ser179Cys
NP_001268422.1:p.Ser7Cys
NP_001268423.1:p.Ser7Cys
LRG_219t1:c.926C>G
LRG_219:g.20763C>G
LRG_219p1:p.Ser309Cys
NC_000002.11:g.48026048C>G
NM_000179.2:c.926C>G
p.S309C

Protein change:

S179C

Links:

dbSNP: rs544222338

NCBI 1000 Genomes Browser:

rs544222338

Molecular consequence:

NM_000179.3:c.926C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.536C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.20C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.20C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: MSH6-related disorder
Synonyms:: MSH6-related disorders; MSH6-related condition
Identifiers:

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paraneoplastic antigen Ma1 homolog [Mus musculus]
paraneoplastic antigen Ma1 homolog [Mus musculus]
gi|148287013|ref|NP_081714.2|

Protein
Sertm1 serine rich and transmembrane domain containing 1 [Mus musculus]
Sertm1 serine rich and transmembrane domain containing 1 [Mus musculus]
Gene ID:329641

Gene
329641[uid] AND (alive[prop]) (1)
Gene
Profile neighbors for GEO Profiles (Select 6124914) (199)
GEO Profiles
PMC Links for GEO Profiles (Select 34520996) (17)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004117970	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 31, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004117970

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 31, 2023)

germline

clinical testing

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

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

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 PreventionGenetics, part of Exact Sciences, SCV004117970.1

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

Description

The MSH6 c.926C>G variant is predicted to result in the amino acid substitution p.Ser309Cys. This variant has been reported in at least one individual with advanced cancer (Mandelker et al. 2017. PubMed ID: 28873162) and in a patient with ovarian cancer (Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also reported in two individuals with endometrial cancer; however, immunohistochemistry of the tumor found one individual had normal MSH6 staining while MSH6 was absent in the other (Chao et al. 2019. PubMed ID: 31307542). This variant is reported in 0.24% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026048-C-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127607/). At this time, while we suspect this variant could be benign (based on minor allele frequency) the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#	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: Nov 3, 2024

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