NM_000179.3(MSH6):c.3238_3239del (p.Leu1080fs) AND Lynch syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 14, 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:: RCV000500492.5

Allele description [Variation Report for NM_000179.3(MSH6):c.3238_3239del (p.Leu1080fs)]

NM_000179.3(MSH6):c.3238_3239del (p.Leu1080fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3238_3239del (p.Leu1080fs)

HGVS:

NC_000002.12:g.47803485_47803486del
NG_007111.1:g.25339_25340del
NM_000179.3:c.3238_3239delMANE SELECT
NM_001281492.2:c.2848_2849del
NM_001281493.2:c.2332_2333del
NM_001281494.2:c.2332_2333del
NP_000170.1:p.Leu1080fs
NP_000170.1:p.Leu1080fs
NP_001268421.1:p.Leu950fs
NP_001268422.1:p.Leu778fs
NP_001268423.1:p.Leu778fs
LRG_219t1:c.3238_3239del
LRG_219:g.25339_25340del
LRG_219p1:p.Leu1080fs
NC_000002.11:g.48030623_48030624del
NC_000002.11:g.48030624_48030625del
NC_000002.12:g.47803485_47803486delCT
NM_000179.2:c.3238_3239del
NM_000179.2:c.3238_3239delCT

Protein change:

L1080fs

Links:

dbSNP: rs863225406

NCBI 1000 Genomes Browser:

rs863225406

Molecular consequence:

NM_000179.3:c.3238_3239del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.2848_2849del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2332_2333del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2332_2333del - 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
SCV000592628	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV004848298	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 14, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24933100, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000592628

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Pathogenic

unknown

clinical testing

SCV004848298

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Oct 14, 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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592628.2

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

Description

The p.Leu1080ValfsX12 variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), Clinvitae, COSMIC, MutDB, â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºMMR Gene Unclassified Variants Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, â€šÃ„ÃºZhejiang Colon Cancer Databaseâ€šÃ„Ã¹, the ClinVar and UMD databases. The p.Leu1080ValfsX12 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1080 and leads to a premature stop codon 12 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848298.1

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

Description

The p.Leu1080ValfsX12 variant in MSH6 has been reported in 1 individual with endometrial cancer (Batte 2014) and was absent from large population studies. This variant has been reported in ClinVar (Variation ID 218060), classified as pathogenic by several clinical labs. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1080 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Leu1080ValfsX12 variant meets criteria to be classified as likely pathogenic for 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 16, 2024

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