NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del) AND Lynch syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 18, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000515764.8

Allele description [Variation Report for NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)]

NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)

HGVS:

NC_000002.11:g.48026740_48026742del
NC_000002.12:g.47799598CTT[1]
NG_007111.1:g.21452CTT[1]
NM_000179.3:c.1615CTT[1]MANE SELECT
NM_001281492.2:c.1225CTT[1]
NM_001281493.2:c.709CTT[1]
NM_001281494.2:c.709CTT[1]
NP_000170.1:p.Leu540del
NP_001268421.1:p.Leu410del
NP_001268422.1:p.Leu238del
NP_001268423.1:p.Leu238del
LRG_219:g.21452CTT[1]
NC_000002.11:g.48026736_48026738del
NC_000002.11:g.48026737CTT[1]
NC_000002.11:g.48026740_48026742del
NM_000179.2:c.1618_1620delCTT
NM_000179.3:c.1618_1620delMANE SELECT

Protein change:

L238del

Links:

dbSNP: rs1064793600

NCBI 1000 Genomes Browser:

rs1064793600

Molecular consequence:

NM_000179.3:c.1615CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.1225CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.709CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.709CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

TTHA0039[sym] AND (alive[prop]) (1)
Gene
TTH_RS00210 [Thermus thermophilus HB8]
TTH_RS00210 [Thermus thermophilus HB8]
Gene ID:3168523

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611879	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Pathogenic (Mar 28, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000920456	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Pathogenic (Oct 18, 2018)	germline	curation	Citation Link,
SCV004834317	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32635641, 34787334, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611879

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Tsai GJ et al. (Genet Med 2018))

Pathogenic
(Mar 28, 2018)

germline

research

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

SCV000920456

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Pathogenic
(Oct 18, 2018)

germline

curation

Citation Link,

SCV004834317

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (3)
[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	1	not provided	not provided	108544	not provided	clinical testing
not provided	germline	no	not provided	1	not provided	not provided	yes	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals.

Dámaso E, González-Acosta M, Vargas-Parra G, Navarro M, Balmaña J, Ramon Y Cajal T, Tuset N, Thompson BA, Marín F, Fernández A, Gómez C, Velasco À, Solanes A, Iglesias S, Urgel G, López C, Del Valle J, Campos O, Santacana M, Matias-Guiu X, Lázaro C, Valle L, et al.

Cancers (Basel). 2020 Jul 5;12(7). doi:pii: E1799. 10.3390/cancers12071799.

PubMed [citation]

PMID:: 32635641
PMCID:: PMC7408773

See all PubMed Citations (4)

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000611879.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	yes	research	PubMed (1)

Description

The MSH6 variant designated as NM_000179.2:c.1618_1620del (p.Leu540del) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and gives a likelihood of 1.838 to 1, which supports pathogenicity (Thompson et al, 2003, PMID:12900794). In addition, endometrial and colorectal tumors from an affected individual in the family contained the germline MHS6 p.Leu540del variant. Each tumor had microsatellite instability and had a different independent second heterozygous pathogenic mutation in MSH6. Each of these observations supports classification of pathogenicity. In addition, this variant has previously been reported in two MSI high tumors with lack of MSH6 staining on IHC (http://www.umd.be/). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and increase cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	1	not provided

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000920456.1

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

Description

Multifactorial likelihood analysis posterior probability > 0.99 (0.992)

#	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 All of Us Research Program, National Institutes of Health, SCV004834317.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This variant causes a deletion of one amino acid in exon 4 of the MSH6 protein. This variant has been observed in several individual affected with Lynch sydrome-associated cancer (PMID: 32635641; ClinVar SCV000580277.5), with tumors that exhibited microsatellite instability and/or loss of MSH6 proteins by immunohistochemistry analyses. RNA analysis demonstrated the presence of an aberrant transcript at low proportion alongside the full-length transcript (PMID: 32635641). This variant has also been observed in homozygous state in individuals affected with autosomal recessive constitutional mismatch mismatch repair deficiency (PMID: 34787334; ClinVar SCV000813105.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Aug 11, 2024

ClinVar

Relating variation to medicine