NM_000179.3(MSH6):c.667A>G (p.Asn223Asp) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 8, 2020
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:: RCV001201254.2

Allele description [Variation Report for NM_000179.3(MSH6):c.667A>G (p.Asn223Asp)]

NM_000179.3(MSH6):c.667A>G (p.Asn223Asp)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.667A>G (p.Asn223Asp)

HGVS:

NC_000002.12:g.47798650A>G
NG_007111.1:g.20504A>G
NM_000179.3:c.667A>GMANE SELECT
NM_001281492.2:c.277A>G
NM_001281493.2:c.-240A>G
NM_001281494.2:c.-240A>G
NP_000170.1:p.Asn223Asp
NP_000170.1:p.Asn223Asp
NP_001268421.1:p.Asn93Asp
LRG_219t1:c.667A>G
LRG_219:g.20504A>G
LRG_219p1:p.Asn223Asp
NC_000002.11:g.48025789A>G
NM_000179.2:c.667A>G

Protein change:

N223D

Links:

dbSNP: rs374041375

NCBI 1000 Genomes Browser:

rs374041375

Molecular consequence:

NM_001281493.2:c.-240A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-240A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.667A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.277A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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peptidase S41 [Elizabethkingia bruuniana]
peptidase S41 [Elizabethkingia bruuniana]
gi|1154494965|gnl|PRJNA301708|AYC65 0|gb|AQX86233.1|

Protein
A1Q1_04591 [Trichosporon asahii var. asahii CBS 2479]
A1Q1_04591 [Trichosporon asahii var. asahii CBS 2479]
Gene ID:25988104

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001372356	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 8, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23621914, 26689913 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001372356

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 8, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372356.1

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

Description

Variant summary: MSH6 c.667A>G (p.Asn223Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.667A>G has been reported in the literature in at least one individual affected with lung adenocarcinoma (Lu_2015). This report however does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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 29, 2024

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