NM_000179.3(MSH6):c.4016_4068dup (p.Ile1357delinsLeuValLysGlyGlnLeuTer) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001875982.5

Allele description [Variation Report for NM_000179.3(MSH6):c.4016_4068dup (p.Ile1357delinsLeuValLysGlyGlnLeuTer)]

NM_000179.3(MSH6):c.4016_4068dup (p.Ile1357delinsLeuValLysGlyGlnLeuTer)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.4016_4068dup (p.Ile1357delinsLeuValLysGlyGlnLeuTer)

HGVS:

NC_000002.12:g.47806793_47806845dup
NG_007111.1:g.28647_28699dup
NG_008397.1:g.103832_103884dup
NM_000179.3:c.4016_4068dupMANE SELECT
NM_001281492.2:c.3626_3678dup
NM_001281493.2:c.3110_3162dup
NM_001281494.2:c.3110_3162dup
NP_000170.1:p.Ile1357delinsLeuValLysGlyGlnLeuTer
NP_001268421.1:p.Ile1227delinsLeuValLysGlyGlnLeuTer
NP_001268422.1:p.Ile1055delinsLeuValLysGlyGlnLeuTer
NP_001268423.1:p.Ile1055delinsLeuValLysGlyGlnLeuTer
LRG_219t1:c.4016_4068dup
LRG_219:g.28647_28699dup
NC_000002.11:g.48033930_48033931insGCTAGTGAAAGGTCAACTGTAGATGCTGAAGCTGTCCATAAATTGCTGACTTT
NC_000002.11:g.48033932_48033984dup
NM_000179.2:c.4016_4068dup

Links:

dbSNP: rs1670211088

NCBI 1000 Genomes Browser:

rs1670211088

Molecular consequence:

NM_000179.3:c.4016_4068dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.3626_3678dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281493.2:c.3110_3162dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281494.2:c.3110_3162dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002302039	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26837502, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002302039

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 2023)

germline

clinical testing

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

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

Rapid detection of germline mutations for hereditary gastrointestinal polyposis/cancers using HaloPlex target enrichment and high-throughput sequencing technologies.

Kohda M, Kumamoto K, Eguchi H, Hirata T, Tada Y, Tanakaya K, Akagi K, Takenoshita S, Iwama T, Ishida H, Okazaki Y.

Fam Cancer. 2016 Oct;15(4):553-62. doi: 10.1007/s10689-016-9872-x.

PubMed [citation]

PMID:: 26837502

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002302039.3

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

Description

This sequence change results in a frameshift in the MSH6 gene (p.Ile1357Leufs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the MSH6 protein and extend the protein by 2 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with colon cancer (PMID: 26837502). ClinVar contains an entry for this variant (Variation ID: 921115). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

Last Updated: Mar 5, 2024

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