NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 16, 2023
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:: RCV000202074.15

Allele description [Variation Report for NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)]

NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)

HGVS:

NC_000002.12:g.47806256_47806259del
NG_007111.1:g.28110_28113del
NG_008397.1:g.104419_104422del
NM_000179.3:c.3699_3702delMANE SELECT
NM_001281492.2:c.3309_3312del
NM_001281493.2:c.2793_2796del
NM_001281494.2:c.2793_2796del
NP_000170.1:p.Lys1233fs
NP_001268421.1:p.Lys1103fs
NP_001268422.1:p.Lys931fs
NP_001268423.1:p.Lys931fs
LRG_219:g.28110_28113del
NC_000002.11:g.48033393_48033396del
NC_000002.11:g.48033395_48033398del
NM_000179.2:c.3699_3702delAGAA
NM_000179.3:c.3699_3702del
p.K1233NFS*6
p.Lys1233Asnfs*6
p.Lys1233AsnfsX6

Protein change:

K1103fs

Links:

dbSNP: rs193922343

NCBI 1000 Genomes Browser:

rs193922343

Molecular consequence:

NM_000179.3:c.3699_3702del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3309_3312del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2793_2796del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2793_2796del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000257273	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18389388, 21642682, 24933100, 25213678, 25980754, 28888541, 29922827, 25741868
SCV000279110	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 16, 2023)	germline	clinical testing	Citation Link,
SCV000601584	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 26, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21642682, 25980754, 25430799, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000257273

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000279110

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 16, 2023)

germline

clinical testing

Citation Link,

SCV000601584

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Mar 26, 2021)

unknown

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation spectrum in HNPCC in the Israeli population.

Goldberg Y, Porat RM, Kedar I, Shochat C, Sagi M, Eilat A, Mendelson S, Hamburger T, Nissan A, Hubert A, Kadouri L, Pikarski E, Lerer I, Abeliovich D, Bercovich D, Peretz T.

Fam Cancer. 2008;7(4):309-17. doi: 10.1007/s10689-008-9191-y. Epub 2008 Apr 4.

PubMed [citation]

PMID:: 18389388

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome.

Batte BA, Bruegl AS, Daniels MS, Ring KL, Dempsey KM, Djordjevic B, Luthra R, Fellman BM, Lu KH, Broaddus RR.

Gynecol Oncol. 2014 Aug;134(2):319-25. doi: 10.1016/j.ygyno.2014.06.009. Epub 2014 Jun 14.

PubMed [citation]

PMID:: 24933100
PMCID:: PMC4125501

See all PubMed Citations (10)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257273.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

PP4, PM2, PVS1

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000279110.14

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25980754, 25213678, 27443514, 21642682, 25430799, 28152038, 18389388, 30787465, 29922827, 32719484, 28888541, 35366121)

#	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, SCV000601584.2

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

Description

This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in individuals with Lynch syndrome in the published literature (PMIDs: 25430799 (2015), 25980754 (2015), and 21642682 (2011)). Based on the available information, this variant is classified as pathogenic.

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

Last Updated: Nov 24, 2024

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