NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 15, 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:: RCV000128914.12

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172781	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000903767	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18389388, 21642682, 24933100, 27443514, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172781

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 22, 2022)

germline

clinical testing

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

Citation Link,

SCV000903767

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 15, 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

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

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, et al.

JAMA. 2011 Jun 8;305(22):2304-10. doi: 10.1001/jama.2011.743.

PubMed [citation]

PMID:: 21642682

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000172781.9

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

Description

The c.3699_3702delAGAA (p.K1233Nfs*6) alteration, located in exon 8 (coding exon 8) of the MSH6 gene, consists of a deletion of 4 nucleotides from position 3699 to 3702, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251238) total alleles studied. The highest observed frequency was 0.001% (1/113596) of European (non-Finnish) alleles. This mutation has been reported in multiple families with Lynch syndrome (Bonadona, 2011). Based on the available evidence, this alteration is 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

From Color Diagnostics, LLC DBA Color Health, SCV000903767.4

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

Description

This variant deletes 4 nucleotides in exon 8 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 18389388, 21642682, 24933100, 27443514). This variant has been identified in 1/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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: Nov 24, 2024

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