NM_000179.3(MSH6):c.3951_3952del (p.His1317fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 7, 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:: RCV001381431.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3951_3952del (p.His1317fs)]

NM_000179.3(MSH6):c.3951_3952del (p.His1317fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3951_3952del (p.His1317fs)

HGVS:

NC_000002.12:g.47806601_47806602del
NG_007111.1:g.28455_28456del
NG_008397.1:g.104075_104076del
NM_000179.3:c.3951_3952delMANE SELECT
NM_001281492.2:c.3561_3562del
NM_001281493.2:c.3045_3046del
NM_001281494.2:c.3045_3046del
NP_000170.1:p.His1317fs
NP_001268421.1:p.His1187fs
NP_001268422.1:p.His1015fs
NP_001268423.1:p.His1015fs
LRG_219:g.28455_28456del
NC_000002.11:g.48033739_48033740del
NC_000002.11:g.48033740_48033741del
NM_000179.2:c.3951_3952delTA

Protein change:

H1015fs

Links:

dbSNP: rs1114167790

NCBI 1000 Genomes Browser:

rs1114167790

Molecular consequence:

NM_000179.3:c.3951_3952del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3561_3562del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.3045_3046del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.3045_3046del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001579814	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16034045, 16418736, 18301448, 20587412, 21056691, 21642682, 26318770, 27601186, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001579814

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 7, 2023)

germline

clinical testing

PubMed (9)
[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

Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.

Stormorken AT, Bowitz-Lothe IM, Norèn T, Kure E, Aase S, Wijnen J, Apold J, Heimdal K, Møller P.

J Clin Oncol. 2005 Jul 20;23(21):4705-12.

PubMed [citation]

PMID:: 16034045

Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.

Plaschke J, Linnebacher M, Kloor M, Gebert J, Cremer FW, Tinschert S, Aust DE, von Knebel Doeberitz M, Schackert HK.

Eur J Hum Genet. 2006 May;14(5):561-6.

PubMed [citation]

PMID:: 16418736

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001579814.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Arg1331*) have been determined to be pathogenic (PMID: 16034045, 16418736, 18301448, 20587412, 21056691, 21642682, 26318770, 27601186). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428429). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1317Glnfs*7) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the MSH6 protein.

#	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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