NM_000179.3(MSH6):c.3727A>T (p.Thr1243Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Aug 12, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000588959.46

Allele description [Variation Report for NM_000179.3(MSH6):c.3727A>T (p.Thr1243Ser)]

NM_000179.3(MSH6):c.3727A>T (p.Thr1243Ser)

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.3727A>T (p.Thr1243Ser)

Other names:

p.T1243S:ACA>TCA

HGVS:

NC_000002.12:g.47806284A>T
NG_007111.1:g.28138A>T
NG_008397.1:g.104392T>A
NM_000179.3:c.3727A>TMANE SELECT
NM_001281492.2:c.3337A>T
NM_001281493.2:c.2821A>T
NM_001281494.2:c.2821A>T
NP_000170.1:p.Thr1243Ser
NP_000170.1:p.Thr1243Ser
NP_001268421.1:p.Thr1113Ser
NP_001268422.1:p.Thr941Ser
NP_001268423.1:p.Thr941Ser
LRG_219t1:c.3727A>T
LRG_219:g.28138A>T
LRG_219p1:p.Thr1243Ser
NC_000002.11:g.48033423A>T
NM_000179.2:c.3727A>T
p.T1243S

Protein change:

T1113S

Links:

dbSNP: rs147453999

NCBI 1000 Genomes Browser:

rs147453999

Molecular consequence:

NM_000179.3:c.3727A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3337A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2821A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2821A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149328	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Oct 6, 2020)	germline	clinical testing	Citation Link,
SCV000805896	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001469575	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely benign (Jun 10, 2023)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23621914, 28687356, 23047549, 33558524, 32658311, 31159747, 26689913, 33471991, 26467025
SCV001473594	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Oct 24, 2019)	germline	clinical testing	Citation Link,
SCV001501271	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (May 1, 2024)	germline	clinical testing	Citation Link,
SCV005411718	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 12, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23047549, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20(1):25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.

Betti M, Casalone E, Ferrante D, Aspesi A, Morleo G, Biasi A, Sculco M, Mancuso G, Guarrera S, Righi L, Grosso F, Libener R, Pavesi M, Mariani N, Casadio C, Boldorini R, Mirabelli D, Pasini B, Magnani C, Matullo G, Dianzani I.

Cancer Lett. 2017 Oct 1;405:38-45. doi: 10.1016/j.canlet.2017.06.028. Epub 2017 Jul 4.

PubMed [citation]

PMID:: 28687356

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000149328.17

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23047549, 23621914, 28687356, 26338694, 31159747)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000805896.1

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

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469575.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473594.1

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

Description

The MSH6 c.3727A>T; p.Thr1243Ser variant (rs147453999) is reported in the literature in individuals with hereditary cancer predisposition syndrome, ovarian cancer, or mesothelioma (Betti 2017, Pal 2012, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 127589). It is found in the general South Asian population with an allele frequency of 0.1% (35/30614 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 1243 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Betti M et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 2017 Oct 1;405:38-45. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001501271.23

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

Description

MSH6: BP1, BS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV005411718.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (2)

Description

BS1

#	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		5	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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