NM_000179.3(MSH6):c.2555AGA[2] (p.Lys854del) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 15, 2018
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:: RCV000656896.1

Allele description

NM_000179.3(MSH6):c.2555AGA[2] (p.Lys854del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.2555AGA[2] (p.Lys854del)

HGVS:

NC_000002.12:g.47800538AGA[2]
NG_007111.1:g.22392AGA[2]
NM_000179.3:c.2555AGA[2]MANE SELECT
NM_001281492.2:c.2165AGA[2]
NM_001281493.2:c.1649AGA[2]
NM_001281494.2:c.1649AGA[2]
NP_000170.1:p.Lys854del
NP_001268421.1:p.Lys724del
NP_001268422.1:p.Lys552del
NP_001268423.1:p.Lys552del
LRG_219:g.22392AGA[2]
NC_000002.11:g.48027676_48027678del
NC_000002.11:g.48027677AGA[2]
NM_000179.2:c.2561_2563delAGA
NM_000179.3:c.2561_2563delAGAMANE SELECT
p.K854del

Protein change:

K552del

Links:

dbSNP: rs587782858

NCBI 1000 Genomes Browser:

rs587782858

Molecular consequence:

NM_000179.3:c.2555AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.2165AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.1649AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.1649AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565226	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000888259	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics Criteria)	Uncertain significance (May 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000565226

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV000888259

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics Criteria)

Uncertain significance
(May 15, 2018)

germline

clinical testing

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

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, SCV000565226.5

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

Description

This deletion of three nucleotides in MSH6 is denoted c.2561_2563delAGA at the cDNA level and p.Lys854del at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delAGA]TTAT. Although this variant was observed in a case of possible constitutional mismatch repair deficiency (CMMR-D), sequencing and deletion/duplication of all mismatch repair genes were not performed and therefore this variant may not be responsible for the phenotype (Bougeard 2014). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This in-frame deletion of a single Lysine residue is located in the lever domain (Warren 2007, Kansikas 2010). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Lys854del to be a variant of uncertain significance.

#	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, SCV000888259.1

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

#	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: Jun 15, 2021

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