NM_000179.3(MSH6):c.2079dup (p.Cys694fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 9, 2021
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:: RCV000167251.10

Allele description [Variation Report for NM_000179.3(MSH6):c.2079dup (p.Cys694fs)]

NM_000179.3(MSH6):c.2079dup (p.Cys694fs)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.2079dup (p.Cys694fs)

HGVS:

NC_000002.12:g.47800062dup
NG_007111.1:g.21916dup
NM_000179.3:c.2079dupMANE SELECT
NM_001281492.2:c.1689dup
NM_001281493.2:c.1173dup
NM_001281494.2:c.1173dup
NP_000170.1:p.Cys694fs
NP_001268421.1:p.Cys564fs
NP_001268422.1:p.Cys392fs
NP_001268423.1:p.Cys392fs
LRG_219:g.21916dup
NC_000002.11:g.48027195_48027196insA
NC_000002.11:g.48027201dup
NC_000002.12:g.47800062_47800063insA
NM_000179.2:c.2079dupA
NM_000179.3:c.2079dup
p.C694MFS*4

Protein change:

C392fs

Links:

dbSNP: rs267608083

NCBI 1000 Genomes Browser:

rs267608083

Molecular consequence:

NM_000179.3:c.2079dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.1689dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.1173dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.1173dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000218091	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 9, 2021)	germline	clinical testing	Citation Link,
SCV001347252	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]
SCV002535694	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Apr 20, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 28195393, 28944238, 18269114, 24362816 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218091

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 9, 2021)

germline

clinical testing

Citation Link,

SCV001347252

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]

SCV002535694

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Apr 20, 2021)

germline

curation

PubMed (4)
[See all records that cite these PMIDs]

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

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

Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.

Hansen MF, Johansen J, Sylvander AE, Bjørnevoll I, Talseth-Palmer BA, Lavik LAS, Xavier A, Engebretsen LF, Scott RJ, Drabløs F, Sjursen W.

Clin Genet. 2017 Oct;92(4):405-414. doi: 10.1111/cge.12994. Epub 2017 Mar 22.

PubMed [citation]

PMID:: 28195393

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000218091.8

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

Description

The c.2079dupA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of A at nucleotide position 2079, causing a translational frameshift with a predicted alternate stop codon (p.C694Mfs*4). This mutation has been detected in multiple colorectal cancer patients (DeRycke MS et al. Mol Genet Genomic Med. 2017 Jul 23;5:553-569; Hansen MF et al. Clin Genet. 2017 Oct;92:405-414). Of note, this alteration is designated as c.2073_2074insA in published literature. 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, SCV001347252.2

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

Description

This variant inserts 1 nucleotide in exon 4 of the MSH6 gene, creating a frameshift and 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

From Sema4, Sema4, SCV002535694.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

#	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: May 7, 2024

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