NM_000179.3(MSH6):c.2295C>A (p.Cys765Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 24, 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:: RCV001184647.5

Allele description [Variation Report for NM_000179.3(MSH6):c.2295C>A (p.Cys765Ter)]

NM_000179.3(MSH6):c.2295C>A (p.Cys765Ter)

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.2295C>A (p.Cys765Ter)

HGVS:

NC_000002.12:g.47800278C>A
NG_007111.1:g.22132C>A
NM_000179.3:c.2295C>AMANE SELECT
NM_001281492.2:c.1905C>A
NM_001281493.2:c.1389C>A
NM_001281494.2:c.1389C>A
NP_000170.1:p.Cys765Ter
NP_000170.1:p.Cys765Ter
NP_001268421.1:p.Cys635Ter
NP_001268422.1:p.Cys463Ter
NP_001268423.1:p.Cys463Ter
LRG_219t1:c.2295C>A
LRG_219:g.22132C>A
LRG_219p1:p.Cys765Ter
NC_000002.11:g.48027417C>A
NM_000179.2:c.2295C>A

Protein change:

C463*

Links:

dbSNP: rs63750985

NCBI 1000 Genomes Browser:

rs63750985

Molecular consequence:

NM_000179.3:c.2295C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.1905C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281493.2:c.1389C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281494.2:c.1389C>A - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

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Homo sapiens gametogenetin binding protein 2 (GGNBP2), mRNA
Homo sapiens gametogenetin binding protein 2 (GGNBP2), mRNA
gi|302191628|ref|NM_024835.3|

Nucleotide
PREDICTED: Mus musculus RIMS binding protein 2 (Rimbp2), transcript variant X7, ...
PREDICTED: Mus musculus RIMS binding protein 2 (Rimbp2), transcript variant X7, mRNA
gi|1720413330|ref|XM_006504296.3|

Nucleotide
DC182884 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone st65n1...
DC182884 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone st65n15 5', mRNA sequence
gi|119159436|gnl|dbEST|43423910|dbj 2884.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001350674	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003867473	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 24, 2023)	germline	clinical testing	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

SCV001350674

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 7, 2019)

germline

clinical testing

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

SCV003867473

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 24, 2023)

germline

clinical testing

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

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

Lynch Syndrome in Thai Endometrial Cancer Patients.

Manchana T, Ariyasriwatana C, Triratanachat S, Phowthongkum P.

Asian Pac J Cancer Prev. 2021 May 1;22(5):1477-1483. doi: 10.31557/APJCP.2021.22.5.1477.

PubMed [citation]

PMID:: 34048176
PMCID:: PMC8408393

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001350674.2

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

Description

This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

#	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 Ambry Genetics, SCV003867473.2

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

Description

The p.C765* pathogenic mutation (also known as c.2295C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 2295. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been identified in a Thai endometrial cancer cohort (Manchana T et al. Asian Pac J Cancer Prev, 2021 May;22:1477-1483). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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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