NM_000179.3(MSH6):c.3920_3923dup (p.Pro1309fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 15, 2022
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:: RCV001388972.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3920_3923dup (p.Pro1309fs)]

NM_000179.3(MSH6):c.3920_3923dup (p.Pro1309fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3920_3923dup (p.Pro1309fs)

HGVS:

NC_000002.11:g.48033708_48033709insATCT
NC_000002.12:g.47806570_47806573dup
NG_007111.1:g.28424_28427dup
NG_008397.1:g.104103_104106dup
NM_000179.3:c.3920_3923dupMANE SELECT
NM_001281492.2:c.3530_3533dup
NM_001281493.2:c.3014_3017dup
NM_001281494.2:c.3014_3017dup
NP_000170.1:p.Pro1309fs
NP_001268421.1:p.Pro1179fs
NP_001268422.1:p.Pro1007fs
NP_001268423.1:p.Pro1007fs
LRG_219t1:c.3923_3924insATCT
LRG_219:g.28424_28427dup
NC_000002.11:g.48033708_48033709insATCT
NC_000002.11:g.48033709_48033712dup
NC_000002.11:g.48033709_48033712dup
NC_000002.11:g.48033712_48033713insATCT
NM_000179.2:c.3920_3923dupATCT
NM_000179.2:c.3923_3924insATCT
p.Pro1309SerfsX11

Protein change:

P1007fs

Links:

dbSNP: rs1572747278

NCBI 1000 Genomes Browser:

rs1572747278

Molecular consequence:

NM_000179.3:c.3920_3923dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3530_3533dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.3014_3017dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.3014_3017dup - 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
SCV001590166	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24323032, 18809606, 26866578, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590166

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2022)

germline

clinical testing

PubMed (4)
[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

Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.

Buchanan DD, Tan YY, Walsh MD, Clendenning M, Metcalf AM, Ferguson K, Arnold ST, Thompson BA, Lose FA, Parsons MT, Walters RJ, Pearson SA, Cummings M, Oehler MK, Blomfield PB, Quinn MA, Kirk JA, Stewart CJ, Obermair A, Young JP, Webb PM, Spurdle AB.

J Clin Oncol. 2014 Jan 10;32(2):90-100. doi: 10.1200/JCO.2013.51.2129. Epub 2013 Dec 9.

PubMed [citation]

PMID:: 24323032
PMCID:: PMC4876359

Feasibility of screening for Lynch syndrome among patients with colorectal cancer.

Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A.

J Clin Oncol. 2008 Dec 10;26(35):5783-8. doi: 10.1200/JCO.2008.17.5950. Epub 2008 Sep 22.

PubMed [citation]

PMID:: 18809606
PMCID:: PMC2645108

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590166.4

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

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.Arg1334Hisfs*14) have been determined to be pathogenic (PMID: 24323032; Invitae). 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: 667011). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18809606, 26866578). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1309Serfs*11) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 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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