NM_000179.3(MSH6):c.3798_3801+9del AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 3, 2018
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:: RCV000698150.14

Allele description [Variation Report for NM_000179.3(MSH6):c.3798_3801+9del]

NM_000179.3(MSH6):c.3798_3801+9del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3798_3801+9del

HGVS:

NC_000002.12:g.47806355_47806367del
NG_007111.1:g.28209_28221del
NG_008397.1:g.104311_104323del
NM_000179.2:c.3798_3801+9del13
NM_000179.3:c.3798_3801+9delMANE SELECT
NM_001281492.2:c.3408_3411+9del
NM_001281493.2:c.2892_2895+9del
NM_001281494.2:c.2892_2895+9del
LRG_219t1:c.3798_3801+9del
LRG_219:g.28209_28221del
NC_000002.11:g.48033492_48033504del
NC_000002.11:g.48033494_48033506del
NM_000179.2:c.3798_3801+9del
NM_000179.2:c.3798_3801+9del13
NM_000179.2:c.3798_3801+9delTATGGTATGTGCA

Links:

dbSNP: rs1553333168

NCBI 1000 Genomes Browser:

rs1553333168

Molecular consequence:

NM_000179.3:c.3798_3801+9del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281492.2:c.3408_3411+9del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281493.2:c.2892_2895+9del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281494.2:c.2892_2895+9del - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000826793	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 3, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18269114, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826793

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 3, 2018)

germline

clinical testing

PubMed (3)
[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

Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.

Devlin LA, Graham CA, Price JH, Morrison PJ.

Ulster Med J. 2008 Jan;77(1):25-30.

PubMed [citation]

PMID:: 18269114
PMCID:: PMC2397009

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]

PMID:: 24362816
PMCID:: PMC4294709

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826793.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 491960). This variant is a deletion of the genomic region encompassing part of exon 8 (c.3798_3801+9del) of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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