NM_000179.3(MSH6):c.972A>C (p.Lys324Asn) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 15, 2023
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:: RCV003997842.2

Allele description [Variation Report for NM_000179.3(MSH6):c.972A>C (p.Lys324Asn)]

NM_000179.3(MSH6):c.972A>C (p.Lys324Asn)

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.972A>C (p.Lys324Asn)

HGVS:

NC_000002.12:g.47798955A>C
NG_007111.1:g.20809A>C
NM_000179.3:c.972A>CMANE SELECT
NM_001281492.2:c.582A>C
NM_001281493.2:c.66A>C
NM_001281494.2:c.66A>C
NP_000170.1:p.Lys324Asn
NP_000170.1:p.Lys324Asn
NP_001268421.1:p.Lys194Asn
NP_001268422.1:p.Lys22Asn
NP_001268423.1:p.Lys22Asn
LRG_219t1:c.972A>C
LRG_219:g.20809A>C
LRG_219p1:p.Lys324Asn
NC_000002.11:g.48026094A>C
NM_000179.2:c.972A>C

Protein change:

K194N

Links:

dbSNP: rs876658610

NCBI 1000 Genomes Browser:

rs876658610

Molecular consequence:

NM_000179.3:c.972A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.582A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.66A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.66A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV004837503	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25980754, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004837503

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 15, 2023)

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	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

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 All of Us Research Program, National Institutes of Health, SCV004837503.1

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

Description

This missense variant replaces lysine with asparagine at codon 324 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a history of Lynch syndrome associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 1/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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