NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 10, 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:: RCV000700703.9

Allele description [Variation Report for NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)]

NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

HGVS:

NC_000002.12:g.47806464_47806477dup
NG_007111.1:g.28318_28331dup
NG_008397.1:g.104200_104213dup
NM_000179.3:c.3814_3827dupMANE SELECT
NM_001281492.2:c.3424_3437dup
NM_001281493.2:c.2908_2921dup
NM_001281494.2:c.2908_2921dup
NP_000170.1:p.Asp1277fs
NP_000170.1:p.Asp1277fs
NP_001268421.1:p.Asp1147fs
NP_001268422.1:p.Asp975fs
NP_001268423.1:p.Asp975fs
LRG_219t1:c.3814_3827dup
LRG_219:g.28318_28331dup
LRG_219p1:p.Asp1277fs
NC_000002.11:g.48033601_48033602insAGAAAATGAATGTG
NC_000002.11:g.48033603_48033616dup
NM_000179.2:c.3814_3827dup
NM_000179.2:c.3814_3827dupGAAAATGAATGTGA

Protein change:

D1147fs

Links:

dbSNP: rs1558393070

NCBI 1000 Genomes Browser:

rs1558393070

Molecular consequence:

NM_000179.3:c.3814_3827dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3424_3437dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2908_2921dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2908_2921dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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RecName: Full=Protein FAM89A
RecName: Full=Protein FAM89A
gi|221272032|sp|Q14BJ1.2|FA89A_MOUS

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000829470	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14520694, 19851887, 21155762, 24440087, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829470

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 10, 2023)

germline

clinical testing

PubMed (5)
[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

MSH6 germline mutations are rare in colorectal cancer families.

Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA.

Int J Cancer. 2003 Nov 20;107(4):571-9.

PubMed [citation]

PMID:: 14520694

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.

Goldberg Y, Porat RM, Kedar I, Shochat C, Galinsky D, Hamburger T, Hubert A, Strul H, Kariiv R, Ben-Avi L, Savion M, Pikarsky E, Abeliovich D, Bercovich D, Lerer I, Peretz T.

Fam Cancer. 2010 Jun;9(2):141-50. doi: 10.1007/s10689-009-9298-9.

PubMed [citation]

PMID:: 19851887

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829470.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Asp1277Lysfs*55) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 577852). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 21155762, 24440087). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as 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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