NM_000179.3(MSH6):c.742dup (p.Arg248fs) AND Lynch syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 8, 2019
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:: RCV004017777.2

Allele description [Variation Report for NM_000179.3(MSH6):c.742dup (p.Arg248fs)]

NM_000179.3(MSH6):c.742dup (p.Arg248fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.742dup (p.Arg248fs)

HGVS:

NC_000002.12:g.47798725dup
NG_007111.1:g.20579dup
NM_000179.3:c.742dupMANE SELECT
NM_001281492.2:c.352dup
NM_001281493.2:c.-165dup
NM_001281494.2:c.-165dup
NP_000170.1:p.Arg248fs
NP_001268421.1:p.Arg118fs
LRG_219t1:c.742dup
LRG_219:g.20579dup
NC_000002.11:g.48025863_48025864insC
NC_000002.11:g.48025864dup
NC_000002.12:g.47798725_47798726insC
NM_000179.2:c.742dupC

Protein change:

R118fs

Links:

dbSNP: rs1572720192

NCBI 1000 Genomes Browser:

rs1572720192

Molecular consequence:

NM_001281493.2:c.-165dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-165dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.742dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.352dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847762	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847762

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 8, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847762.1

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

Description

The p.Arg248ProfsX8 variant in MSH6 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 248 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg248ProfsX8 variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1; PM2.

#	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: Sep 29, 2024

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