NM_000179.3(MSH6):c.3732_3735dup (p.Ser1246fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 25, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000486504.6

Allele description [Variation Report for NM_000179.3(MSH6):c.3732_3735dup (p.Ser1246fs)]

NM_000179.3(MSH6):c.3732_3735dup (p.Ser1246fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3732_3735dup (p.Ser1246fs)

HGVS:

NC_000002.12:g.47806289_47806292dup
NG_007111.1:g.28143_28146dup
NG_008397.1:g.104386_104389dup
NM_000179.3:c.3732_3735dupMANE SELECT
NM_001281492.2:c.3342_3345dup
NM_001281493.2:c.2826_2829dup
NM_001281494.2:c.2826_2829dup
NP_000170.1:p.Ser1246fs
NP_000170.1:p.Ser1246fs
NP_001268421.1:p.Ser1116fs
NP_001268422.1:p.Ser944fs
NP_001268423.1:p.Ser944fs
LRG_219t1:c.3732_3735dup
LRG_219:g.28143_28146dup
LRG_219p1:p.Ser1246fs
NC_000002.11:g.48033425_48033426insTTAT
NC_000002.11:g.48033428_48033431dup
NM_000179.2:c.3732_3735dup
NM_000179.2:c.3732_3735dupATTT

Protein change:

S1116fs

Links:

dbSNP: rs1553333072

NCBI 1000 Genomes Browser:

rs1553333072

Molecular consequence:

NM_000179.3:c.3732_3735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3342_3345dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2826_2829dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2826_2829dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000566245	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 3, 2018)	germline	clinical testing	Citation Link,
SCV001134440	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Apr 25, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29345684, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000566245

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Dec 3, 2018)

germline

clinical testing

Citation Link,

SCV001134440

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Apr 25, 2019)

germline

clinical testing

PubMed (2)
[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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.

Roberts ME, Jackson SA, Susswein LR, Zeinomar N, Ma X, Marshall ML, Stettner AR, Milewski B, Xu Z, Solomon BD, Terry MB, Hruska KS, Klein RT, Chung WK.

Genet Med. 2018 Oct;20(10):1167-1174. doi: 10.1038/gim.2017.254. Epub 2018 Jan 18.

PubMed [citation]

PMID:: 29345684
PMCID:: PMC6051923

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000566245.4

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

Description

This duplication of four nucleotides in MSH6 is denoted c.3732_3735dupATTT at the cDNA level and p.Ser1246IlefsX30 (S1246IfsX30) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CATT[dupATTT]TCAA. The duplication causes a frameshift which changes a Serine to an Isoleucine at codon 1246, and creates a premature stop codon at position 30 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3732_3735dupATTT has been reported in an unaffected individual undergoing multi-gene panel testing due to a family history of cancer (Roberts 2018). We consider this variant to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134440.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Frequency is consistent with pathogenicity. Seen in at least one patient.

#	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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