NM_000179.3(MSH6):c.3740C>G (p.Thr1247Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000214013.13

Allele description [Variation Report for NM_000179.3(MSH6):c.3740C>G (p.Thr1247Ser)]

NM_000179.3(MSH6):c.3740C>G (p.Thr1247Ser)

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.3740C>G (p.Thr1247Ser)

HGVS:

NC_000002.12:g.47806297C>G
NG_007111.1:g.28151C>G
NG_008397.1:g.104379G>C
NM_000179.3:c.3740C>GMANE SELECT
NM_001281492.2:c.3350C>G
NM_001281493.2:c.2834C>G
NM_001281494.2:c.2834C>G
NP_000170.1:p.Thr1247Ser
NP_000170.1:p.Thr1247Ser
NP_001268421.1:p.Thr1117Ser
NP_001268422.1:p.Thr945Ser
NP_001268423.1:p.Thr945Ser
LRG_219t1:c.3740C>G
LRG_219:g.28151C>G
LRG_219p1:p.Thr1247Ser
NC_000002.11:g.48033436C>G
NM_000179.2:c.3740C>G

Protein change:

T1117S

Links:

dbSNP: rs786204182

NCBI 1000 Genomes Browser:

rs786204182

Molecular consequence:

NM_000179.3:c.3740C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3350C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2834C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2834C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276887	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000685439	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 25741868
SCV002528060	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Feb 17, 2022)	germline	curation	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

SCV000276887

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 23, 2023)

germline

clinical testing

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

Citation Link,

SCV000685439

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 20, 2023)

germline

clinical testing

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

SCV002528060

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Feb 17, 2022)

germline

curation

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, curation

Citations

PubMed

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

Cremin C, Lee MK, Hong Q, Hoeschen C, Mackenzie A, Dixon K, McCullum M, Nuk J, Kalloger S, Karasinska J, Scudamore C, Kim PTW, Donnellan F, Lam ECS, Lim HJ, Neben CL, Stedden W, Zhou AY, Schaeffer DF, Sun S, Renouf DJ, Schrader KA.

Cancer Med. 2020 Jun;9(11):4004-4013. doi: 10.1002/cam4.2973. Epub 2020 Apr 7.

PubMed [citation]

PMID:: 32255556
PMCID:: PMC7286471

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000276887.8

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

Description

The p.T1247S variant (also known as c.3740C>G), located in coding exon 8 of the MSH6 gene, results from a C to G substitution at nucleotide position 3740. The threonine at codon 1247 is replaced by serine, an amino acid with similar properties. This variant was identified in 1/177 individuals with pancreatic ductal adenocarcinoma undergoing multi-gene panel testing (Cremin C et al. Cancer Med, 2020 Jun;9:4004-4013). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685439.5

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

Description

This missense variant replaces threonine with serine at codon 1247 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has not been identified 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002528060.1

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

Last Updated: Oct 8, 2024

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