NM_000179.3(MSH6):c.3815A>C (p.Glu1272Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 17, 2022
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:: RCV002355274.3

Allele description [Variation Report for NM_000179.3(MSH6):c.3815A>C (p.Glu1272Ala)]

NM_000179.3(MSH6):c.3815A>C (p.Glu1272Ala)

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.3815A>C (p.Glu1272Ala)

HGVS:

NC_000002.12:g.47806465A>C
NG_007111.1:g.28319A>C
NG_008397.1:g.104211T>G
NM_000179.3:c.3815A>CMANE SELECT
NM_001281492.2:c.3425A>C
NM_001281493.2:c.2909A>C
NM_001281494.2:c.2909A>C
NM_001406795.1:c.3911A>C
NM_001406796.1:c.3815A>C
NM_001406797.1:c.3518A>C
NM_001406798.1:c.3641A>C
NM_001406799.1:c.3290A>C
NM_001406800.1:c.3802A>C
NM_001406801.1:c.3518A>C
NM_001406803.1:c.2951A>C
NM_001406804.1:c.3737A>C
NM_001406805.1:c.3518A>C
NM_001406806.1:c.3290A>C
NM_001406807.1:c.3290A>C
NM_001406808.1:c.3815A>C
NM_001406809.1:c.3815A>C
NM_001406811.1:c.2909A>C
NM_001406812.1:c.2909A>C
NM_001406813.1:c.3821A>C
NM_001406814.1:c.2909A>C
NM_001406815.1:c.2909A>C
NM_001406816.1:c.2909A>C
NM_001406817.1:c.2249A>C
NM_001406818.1:c.3518A>C
NM_001406819.1:c.3518A>C
NM_001406820.1:c.3518A>C
NM_001406821.1:c.3518A>C
NM_001406822.1:c.3518A>C
NM_001406823.1:c.2909A>C
NM_001406824.1:c.3518A>C
NM_001406825.1:c.3518A>C
NM_001406826.1:c.3647A>C
NM_001406827.1:c.3518A>C
NM_001406828.1:c.3518A>C
NM_001406829.1:c.2909A>C
NM_001406830.1:c.3518A>C
NM_001406831.1:c.596A>C
NM_001406832.1:c.662A>C
NM_001407362.1:c.1760A>C
NP_000170.1:p.Glu1272Ala
NP_000170.1:p.Glu1272Ala
NP_001268421.1:p.Glu1142Ala
NP_001268422.1:p.Glu970Ala
NP_001268423.1:p.Glu970Ala
NP_001393724.1:p.Glu1304Ala
NP_001393725.1:p.Glu1272Ala
NP_001393726.1:p.Glu1173Ala
NP_001393727.1:p.Glu1214Ala
NP_001393728.1:p.Glu1097Ala
NP_001393729.1:p.Lys1268Gln
NP_001393730.1:p.Glu1173Ala
NP_001393732.1:p.Glu984Ala
NP_001393733.1:p.Glu1246Ala
NP_001393734.1:p.Glu1173Ala
NP_001393735.1:p.Glu1097Ala
NP_001393736.1:p.Glu1097Ala
NP_001393737.1:p.Glu1272Ala
NP_001393738.1:p.Glu1272Ala
NP_001393740.1:p.Glu970Ala
NP_001393741.1:p.Glu970Ala
NP_001393742.1:p.Glu1274Ala
NP_001393743.1:p.Glu970Ala
NP_001393744.1:p.Glu970Ala
NP_001393745.1:p.Glu970Ala
NP_001393746.1:p.Glu750Ala
NP_001393747.1:p.Glu1173Ala
NP_001393748.1:p.Glu1173Ala
NP_001393749.1:p.Glu1173Ala
NP_001393750.1:p.Glu1173Ala
NP_001393751.1:p.Glu1173Ala
NP_001393752.1:p.Glu970Ala
NP_001393753.1:p.Glu1173Ala
NP_001393754.1:p.Glu1173Ala
NP_001393755.1:p.Glu1216Ala
NP_001393756.1:p.Glu1173Ala
NP_001393757.1:p.Glu1173Ala
NP_001393758.1:p.Glu970Ala
NP_001393759.1:p.Glu1173Ala
NP_001393760.1:p.Glu199Ala
NP_001393761.1:p.Glu221Ala
NP_001394291.1:p.Glu587Ala
LRG_219t1:c.3815A>C
LRG_219:g.28319A>C
LRG_219p1:p.Glu1272Ala
NC_000002.11:g.48033604A>C
NM_000179.2:c.3815A>C
NR_176256.1:n.2745A>C
NR_176257.1:n.4076A>C
NR_176258.1:n.4005A>C
NR_176259.1:n.3904A>C
NR_176260.1:n.1849A>C
NR_176261.1:n.3786A>C

Protein change:

E1097A

Molecular consequence:

NM_000179.3:c.3815A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3425A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.3911A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.3815A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.3641A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.3290A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.3802A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.2951A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.3737A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.3290A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.3290A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.3815A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.3815A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.3821A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406817.1:c.2249A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.3647A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.2909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.3518A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406831.1:c.596A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406832.1:c.662A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407362.1:c.1760A>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002623368	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 20, 2021)	germline	clinical testing	Citation Link,
SCV004357764	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002623368

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 20, 2021)

germline

clinical testing

Citation Link,

SCV004357764

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 17, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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 Ambry Genetics, SCV002623368.2

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

Description

The p.E1272A variant (also known as c.3815A>C), located in coding exon 9 of the MSH6 gene, results from an A to C substitution at nucleotide position 3815. The glutamic acid at codon 1272 is replaced by alanine, an amino acid with dissimilar properties. 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, SCV004357764.1

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

Description

This missense variant replaces glutamic acid with alanine at codon 1272 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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: May 1, 2024

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