NM_000179.3(MSH6):c.3691GTT[1] (p.Val1232del) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 25, 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:: RCV000704903.5

Allele description [Variation Report for NM_000179.3(MSH6):c.3691GTT[1] (p.Val1232del)]

NM_000179.3(MSH6):c.3691GTT[1] (p.Val1232del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3691GTT[1] (p.Val1232del)

HGVS:

NC_000002.12:g.47806248GTT[1]
NG_007111.1:g.28102GTT[1]
NG_008397.1:g.104423AAC[1]
NM_000179.3:c.3691GTT[1]MANE SELECT
NM_001281492.2:c.3301GTT[1]
NM_001281493.2:c.2785GTT[1]
NM_001281494.2:c.2785GTT[1]
NP_000170.1:p.Val1232del
NP_001268421.1:p.Val1102del
NP_001268422.1:p.Val930del
NP_001268423.1:p.Val930del
LRG_219:g.28102GTT[1]
NC_000002.11:g.48033387GTT[1]
NC_000002.11:g.48033387_48033389del
NM_000179.2:c.3694_3696delGTT

Protein change:

V1102del

Links:

dbSNP: rs587779284

NCBI 1000 Genomes Browser:

rs587779284

Molecular consequence:

NM_000179.3:c.3691GTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.3301GTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.2785GTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.2785GTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

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

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ras-related protein Rab-26 [Mus musculus]
ras-related protein Rab-26 [Mus musculus]
gi|254939698|ref|NP_796349.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000833875	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24323032, 28491141, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000833875

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 25, 2023)

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

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

Universal molecular screening does not effectively detect Lynch syndrome in clinical practice.

Brennan B, Hemmings CT, Clark I, Yip D, Fadia M, Taupin DR.

Therap Adv Gastroenterol. 2017 Apr;10(4):361-371. doi: 10.1177/1756283X17690990. Epub 2017 Feb 9.

PubMed [citation]

PMID:: 28491141
PMCID:: PMC5405883

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000833875.4

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

Description

This variant, c.3694_3696del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Val1232del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 24323032, 28491141; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89448). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 8, 2024

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