NM_000179.3(MSH6):c.1729C>T (p.Arg577Cys) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 2024
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:: RCV003997068.2

Allele description [Variation Report for NM_000179.3(MSH6):c.1729C>T (p.Arg577Cys)]

NM_000179.3(MSH6):c.1729C>T (p.Arg577Cys)

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.1729C>T (p.Arg577Cys)

Other names:

p.R577C:CGC>TGC

HGVS:

NC_000002.12:g.47799712C>T
NG_007111.1:g.21566C>T
NM_000179.3:c.1729C>TMANE SELECT
NM_001281492.2:c.1339C>T
NM_001281493.2:c.823C>T
NM_001281494.2:c.823C>T
NP_000170.1:p.Arg577Cys
NP_000170.1:p.Arg577Cys
NP_001268421.1:p.Arg447Cys
NP_001268422.1:p.Arg275Cys
NP_001268423.1:p.Arg275Cys
LRG_219t1:c.1729C>T
LRG_219:g.21566C>T
LRG_219p1:p.Arg577Cys
NC_000002.11:g.48026851C>T
NM_000179.2:c.1729C>T

Protein change:

R275C

Links:

dbSNP: rs542838372

NCBI 1000 Genomes Browser:

rs542838372

Molecular consequence:

NM_000179.3:c.1729C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1339C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.823C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.823C>T - 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
SCV004837795	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18809606, 25133505, 29659569, 32980694, 33008098, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004837795

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (7)
[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	8	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Feasibility of screening for Lynch syndrome among patients with colorectal cancer.

Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A.

J Clin Oncol. 2008 Dec 10;26(35):5783-8. doi: 10.1200/JCO.2008.17.5950. Epub 2008 Sep 22.

PubMed [citation]

PMID:: 18809606
PMCID:: PMC2645108

The mutational spectrum of Lynch syndrome in cyprus.

Loizidou MA, Neophytou I, Papamichael D, Kountourakis P, Vassiliou V, Marcou Y, Kakouri E, Ioannidis G, Philippou C, Spanou E, Tanteles GA, Anastasiadou V, Hadjisavvas A, Kyriacou K.

PLoS One. 2014;9(8):e105501. doi: 10.1371/journal.pone.0105501.

PubMed [citation]

PMID:: 25133505
PMCID:: PMC4136928

See all PubMed Citations (7)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004837795.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces arginine with cysteine at codon 577 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with prostate (PMID: 29659569), ovarian (PMID: 33008098), breast (PMID: 33471991) and colorectal cancer (PMID: 18809606, 25133505). This variant has also been observed in healthy individuals in breast and pancreatic cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 10/281608 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		8	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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