NM_000179.3(MSH6):c.751A>G (p.Ile251Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 2, 2023
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:: RCV000215096.8

Allele description [Variation Report for NM_000179.3(MSH6):c.751A>G (p.Ile251Val)]

NM_000179.3(MSH6):c.751A>G (p.Ile251Val)

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.751A>G (p.Ile251Val)

HGVS:

NC_000002.12:g.47798734A>G
NG_007111.1:g.20588A>G
NM_000179.3:c.751A>GMANE SELECT
NM_001281492.2:c.361A>G
NM_001281493.2:c.-156A>G
NM_001281494.2:c.-156A>G
NP_000170.1:p.Ile251Val
NP_000170.1:p.Ile251Val
NP_001268421.1:p.Ile121Val
LRG_219t1:c.751A>G
LRG_219:g.20588A>G
LRG_219p1:p.Ile251Val
NC_000002.11:g.48025873A>G
NM_000179.2:c.751A>G

Protein change:

I121V

Links:

dbSNP: rs554884560

NCBI 1000 Genomes Browser:

rs554884560

Molecular consequence:

NM_001281493.2:c.-156A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-156A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.361A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Nucleotide
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Nucleotide
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gi|298905898|emb|FQ214027.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000277875	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 27, 2023)	germline	clinical testing	Citation Link,
SCV000911421	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19924528, 35901820, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000277875

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 27, 2023)

germline

clinical testing

Citation Link,

SCV000911421

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 2, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association of rare MSH6 variants with familial breast cancer.

Wasielewski M, Riaz M, Vermeulen J, van den Ouweland A, Labrijn-Marks I, Olmer R, van der Spaa L, Klijn JG, Meijers-Heijboer H, Dooijes D, Schutte M.

Breast Cancer Res Treat. 2010 Sep;123(2):315-20. doi: 10.1007/s10549-009-0634-4. Epub 2009 Nov 19.

PubMed [citation]

PMID:: 19924528

ICGC-ARGO precision medicine: an update on familial matters in pancreatic cancer.

Milella M, Lawlor RT, Luchini C, Johns AL; ICGC-ARGO., Casolino R, Yoshino T, Biankin AV, Scarpa A.

Lancet Oncol. 2022 Aug;23(8):991-992. doi: 10.1016/S1470-2045(22)00448-X. No abstract available.

PubMed [citation]

PMID:: 35901820

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000277875.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.I251V variant (also known as c.751A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in 1/136 families with breast and colon cancer and in 0/332 controls (Wasielewski M et al. Breast Cancer Res Treat. 2010 Sep;123(2):315-20). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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, SCV000911421.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces isoleucine with valine at codon 251 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 a family affected with hereditary breast and colorectal cancer (PMID: 19924528), and in related individuals affected with pancreatic and thyroid cancer (PMID: 35901820). This variant has been identified in 2/251160 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

Last Updated: Oct 8, 2024

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