NM_000179.3(MSH6):c.3477C>A (p.Tyr1159Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 19, 2022
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:: RCV000491158.14

Allele description [Variation Report for NM_000179.3(MSH6):c.3477C>A (p.Tyr1159Ter)]

NM_000179.3(MSH6):c.3477C>A (p.Tyr1159Ter)

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.3477C>A (p.Tyr1159Ter)

Other names:

NP_000170.1:p.Tyr1159*

HGVS:

NC_000002.12:g.47804948C>A
NG_007111.1:g.26802C>A
NG_008397.1:g.105728G>T
NM_000179.3:c.3477C>AMANE SELECT
NM_001281492.2:c.3087C>A
NM_001281493.2:c.2571C>A
NM_001281494.2:c.2571C>A
NP_000170.1:p.Tyr1159Ter
NP_000170.1:p.Tyr1159Ter
NP_001268421.1:p.Tyr1029Ter
NP_001268422.1:p.Tyr857Ter
NP_001268423.1:p.Tyr857Ter
LRG_219t1:c.3477C>A
LRG_219:g.26802C>A
LRG_219p1:p.Tyr1159Ter
NC_000002.11:g.48032087C>A
NM_000179.2:c.3477C>A

Protein change:

Y1029*

Links:

dbSNP: rs398123231

NCBI 1000 Genomes Browser:

rs398123231

Molecular consequence:

NM_000179.3:c.3477C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.3087C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281493.2:c.2571C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001281494.2:c.2571C>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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Mus musculus Werner helicasae interacting protein (Wrnip), mRNA
Mus musculus Werner helicasae interacting protein (Wrnip), mRNA
gi|19920339|ref|NM_030215.1|

Nucleotide
hd28g06.x1 Soares_NFL_T_GBC_S1 Homo sapiens cDNA clone IMAGE:2910874 3', mRNA se...
hd28g06.x1 Soares_NFL_T_GBC_S1 Homo sapiens cDNA clone IMAGE:2910874 3', mRNA sequence
gi|7038942|gnl|dbEST|3879709|gb|AW4 .1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580185	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001340971	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	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

SCV000580185

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 19, 2022)

germline

clinical testing

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

Citation Link,

SCV001340971

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

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

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, et al.

JAMA. 2011 Jun 8;305(22):2304-10. doi: 10.1001/jama.2011.743.

PubMed [citation]

PMID:: 21642682

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 Ambry Genetics, SCV000580185.6

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

Description

The p.Y1159* pathogenic mutation (also known as c.3477C>A), located in coding exon 6 of the MSH6 gene, results from a C to A substitution at nucleotide position 3477. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This mutation was identified in a single French family suspected of Lynch syndrome in one study (Bonadona V et al. JAMA 2011 Jun;305:2304-10). 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

From Color Diagnostics, LLC DBA Color Health, SCV001340971.2

#	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 6 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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 (clinicalgenome.org). Based on the 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

Last Updated: Oct 26, 2024

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