NM_000179.3(MSH6):c.1739C>T (p.Ser580Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 13, 2025
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:: RCV000131189.19

Allele description [Variation Report for NM_000179.3(MSH6):c.1739C>T (p.Ser580Leu)]

NM_000179.3(MSH6):c.1739C>T (p.Ser580Leu)

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.1739C>T (p.Ser580Leu)

HGVS:

NC_000002.12:g.47799722C>T
NG_007111.1:g.21576C>T
NM_000179.3:c.1739C>TMANE SELECT
NM_001281492.2:c.1349C>T
NM_001281493.2:c.833C>T
NM_001281494.2:c.833C>T
NP_000170.1:p.Ser580Leu
NP_000170.1:p.Ser580Leu
NP_001268421.1:p.Ser450Leu
NP_001268422.1:p.Ser278Leu
NP_001268423.1:p.Ser278Leu
LRG_219t1:c.1739C>T
LRG_219:g.21576C>T
LRG_219p1:p.Ser580Leu
NC_000002.11:g.48026861C>T
NM_000179.2:c.1739C>T
P52701:p.Ser580Leu
p.S580L

Protein change:

S278L

Links:

UniProtKB: P52701#VAR_038038; dbSNP: rs41295270

NCBI 1000 Genomes Browser:

rs41295270

Molecular consequence:

NM_000179.3:c.1739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1349C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.833C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.833C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186139	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 18, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18033691, 18269114, 29596542, 30267214, 32980694, 33471991, 34326862, 34687117, 39004446 Citation Link,
SCV000537562	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 13, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18033691, 18269114, 32980694, 33471991, 25741868
SCV002535655	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 2, 2022)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 18033691, 29596542, 31391288, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186139

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 18, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000537562

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 13, 2025)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002535655

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 2, 2022)

germline

curation

PubMed (4)
[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, curation

Citations

PubMed

Rare loss of function variants in candidate genes and risk of colorectal cancer.

Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U, Jarvik GP; NHLBI GO Exome Sequencing Project.

Hum Genet. 2018 Oct;137(10):795-806. doi: 10.1007/s00439-018-1938-4. Epub 2018 Sep 28.

PubMed [citation]

PMID:: 30267214
PMCID:: PMC6283057

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

Bhai P, Levy MA, Rooney K, Carere DA, Reilly J, Kerkhof J, Volodarsky M, Stuart A, Kadour M, Panabaker K, Schenkel LC, Lin H, Ainsworth P, Sadikovic B.

Front Genet. 2021;12:698595. doi: 10.3389/fgene.2021.698595.

PubMed [citation]

PMID:: 34326862
PMCID:: PMC8314385

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000186139.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.S580L variant (also known as c.1739C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in individuals diagnosed with colorectal cancer (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806; Fummey E et al. J Med Genet, 2024 Aug;61:861-869), breast cancer (Bhai P et al. Front Genet, 2021 Jul;12:698595; Dorling et al. N Engl J Med 2021 02;384:428-439). It has also been reported in unaffected control individuals (Dorling et al. N Engl J Med 2021 02;384:428-439; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This variant has also been reported in a HNPCC-like family; however, no other clinical information was provided (Devlin LA et al. Ulster Med J. 2008 Jan;77:25-30). This variant was also reported in an individual with colorectal cancer whose tumor demonstrated loss of expression of MLH1/PMS2 on IHC and intact MSH2/MSH6, in addition to MLH1 promoter hypermethylation and BRAF V600E. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000537562.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces serine with leucine at codon 580 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 two individuals affected with Lynch syndrome-associated cancer, in which one tumor was found to have stable microsatellite markers and had detectable DNA mismatch repair proteins (PMID: 18033691, 18269114). This variant also has been reported in a pancreatic cancer case-control study in 2 unaffected controls and absent in 1005 cancer cases (PMID: 32980694) and a breast cancer case-control study in 5 breast cancer cases and 8 unaffected controls (PMID: 33471991). This variant has been identified in 16/281632 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002535655.1

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

#	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: May 25, 2025

ClinVar

Relating variation to medicine