NM_000179.3(MSH6):c.3232G>C (p.Val1078Leu) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 5, 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:: RCV003997247.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3232G>C (p.Val1078Leu)]

NM_000179.3(MSH6):c.3232G>C (p.Val1078Leu)

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.3232G>C (p.Val1078Leu)

Other names:

p.V1078L:GTA>CTA

HGVS:

NC_000002.12:g.47803479G>C
NG_007111.1:g.25333G>C
NM_000179.3:c.3232G>CMANE SELECT
NM_001281492.2:c.2842G>C
NM_001281493.2:c.2326G>C
NM_001281494.2:c.2326G>C
NP_000170.1:p.Val1078Leu
NP_000170.1:p.Val1078Leu
NP_001268421.1:p.Val948Leu
NP_001268422.1:p.Val776Leu
NP_001268423.1:p.Val776Leu
LRG_219t1:c.3232G>C
LRG_219:g.25333G>C
LRG_219p1:p.Val1078Leu
NC_000002.11:g.48030618G>C
NM_000179.2:c.3232G>C

Protein change:

V1078L

Links:

dbSNP: rs587779932

NCBI 1000 Genomes Browser:

rs587779932

Molecular consequence:

NM_000179.3:c.3232G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2842G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2326G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2326G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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Mus musculus coiled-coil domain containing 51 (Ccdc51), mRNA
Mus musculus coiled-coil domain containing 51 (Ccdc51), mRNA
gi|21313383|ref|NM_025689.1|

Nucleotide
Mus musculus myosin light chain, alkali, cardiac atria (Myla), mRNA
Mus musculus myosin light chain, alkali, cardiac atria (Myla), mRNA
gi|6754775|ref|NM_010858.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004835013	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27153395, 33193653, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004835013

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

germline

clinical testing

PubMed (4)
[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	6	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.

Maxwell KN, Hart SN, Vijai J, Schrader KA, Slavin TP, Thomas T, Wubbenhorst B, Ravichandran V, Moore RM, Hu C, Guidugli L, Wenz B, Domchek SM, Robson ME, Szabo C, Neuhausen SL, Weitzel JN, Offit K, Couch FJ, Nathanson KL.

Am J Hum Genet. 2016 May 5;98(5):801-817. doi: 10.1016/j.ajhg.2016.02.024.

PubMed [citation]

PMID:: 27153395
PMCID:: PMC4863474

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.

Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, Hasselby JP, Wikman F, Okkels H, Skytte AB, Nilbert M, Wadt K, Gerdes AM, van Overeem Hansen T.

Front Genet. 2020;11:566266. doi: 10.3389/fgene.2020.566266.

PubMed [citation]

PMID:: 33193653
PMCID:: PMC7541943

See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004835013.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces valine with leucine at codon 1078 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 affected with breast or ovarian cancer (PMID: 27153395), and in an individual affected with colorectal cancer who also had a pathogenic MUTYH variant (PMID: 33193653). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/282788 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		6	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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