ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(9); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala)
Variation ID: 141327 Accession: VCV000141327.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806781 (GRCh38) [ NCBI UCSC ] 2: 48033920 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 6, 2017 Jun 29, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.4004A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Glu1335Ala missense NM_001281492.2:c.3614A>C NP_001268421.1:p.Glu1205Ala missense NM_001281493.2:c.3098A>C NP_001268422.1:p.Glu1033Ala missense NM_001281494.2:c.3098A>C NP_001268423.1:p.Glu1033Ala missense NC_000002.12:g.47806781A>C NC_000002.11:g.48033920A>C NG_007111.1:g.28635A>C NG_008397.1:g.103895T>G LRG_219:g.28635A>C LRG_219t1:c.4004A>C LRG_219p1:p.Glu1335Ala - Protein change
- E1335A, E1033A, E1205A
- Other names
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- Canonical SPDI
- NC_000002.12:47806780:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9149 | 9460 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000129804.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000204360.11 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 29, 2023 | RCV000409369.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 18, 2019 | RCV000656905.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 13, 2024 | RCV003467121.2 | |
MSH6-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV004532553.2 |
Likely benign (1) |
criteria provided, single submitter
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Mar 26, 2024 | RCV001375525.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Feb 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000339599.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135869.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536312.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.4004A>C (p.E1335A) variant has been reported in several individuals with colorectal, brain, or breast cancer (PMID: 23523604, 24073290, 28528518, 30306255, 32547938). It was … (more)
The MSH6 c.4004A>C (p.E1335A) variant has been reported in several individuals with colorectal, brain, or breast cancer (PMID: 23523604, 24073290, 28528518, 30306255, 32547938). It was also reported in 2/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). This variant was observed in 9/28634 chromosomes in the South Asian population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 141327). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Aug 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489131.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Dec 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565241.6
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 23523604, 28528518, 24073290)
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Uncertain significance
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000685482.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with alanine at codon 1335 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with alanine at codon 1335 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 performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 23523604), astrocytoma (PMID: 24073290), breast and/or ovarian cancer (PMID: 28528518, 32547938) or suspected of having Lynch syndrome (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 22/271900 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. (less)
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Uncertain significance
(Dec 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000261608.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1335 of the MSH6 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1335 of the MSH6 protein (p.Glu1335Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer, astrocytoma, or breast and/or ovarian cancers (PMID: 23523604, 24073290, 28528518, 30306255, 32547938). ClinVar contains an entry for this variant (Variation ID: 141327). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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MSH6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004740703.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MSH6 c.4004A>C variant is predicted to result in the amino acid substitution p.Glu1335Ala. This variant has been reported in individuals with a history of … (more)
The MSH6 c.4004A>C variant is predicted to result in the amino acid substitution p.Glu1335Ala. This variant has been reported in individuals with a history of Lynch syndrome, astrocytoma, and breast and/or ovarian cancer (Rodríguez-Hernández et al. 2013. PubMed ID: 24073290; Pérez-Cabornero et al. 2013. PubMed ID: 23523604; Cock-Rada et al. 2018. PubMed ID: 28528518). This variant is reported in 0.031% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141327/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184615.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E1335A variant (also known as c.4004A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide … (more)
The p.E1335A variant (also known as c.4004A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4004. The glutamic acid at codon 1335 is replaced by alanine, an amino acid with dissimilar properties. This variant was reported in one family that met Amsterdam criteria and segregated with disease. The proband was diagnosed with colon cancer at age 42; however, tumor testing showed wild-type BRAF analysis, microsatellite stability, and normal IHC staining (Pérez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This alteration has also been reported as a variant of unknown significance, detected in a low-grade malignant astrocytoma that showed microsatellite stability and loss of staining for MLH1, MSH2, and MSH6 on IHC (Rodríguez-Hernández I et al. PLoS One. 2013 Sep 20;8(9):e76401). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Cock-Rada AM et al. Fam Cancer, 2018 Jan;17:23-30; Nikitin AG et al. Front Oncol. 2020 May;10:666; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195635.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely benign
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572381.5
First in ClinVar: Apr 30, 2021 Last updated: Jun 29, 2024 |
Comment:
Variant summary: MSH6 c.4004A>C (p.Glu1335Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: MSH6 c.4004A>C (p.Glu1335Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 1590584 control chromosomes, predominantly at a frequency of 0.00036 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch syndrome (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.4004A>C has been reported in the literature in individuals undergoing multigene panel testing for hereditary cancers such as Lynch, low grade astrocytoma and breast (example, Perez-Cabornero_2013, Rodriguez-Hernandez_2013, Cock-Rada_2017, Nikitin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least three co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (BRCA1 c.5266dupC, p.Gln1756Profs, Nikitin_2020; PALB2 c.1317delG, p.Phe440fs, internal testing; CDH1 c.537delA , p.Lys179Asnfs*36, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a "likely benign". The following publications have been ascertained in the context of this evaluation (PMID: 30306255, 28528518, 31391288, 32547938, 23523604, 24073290). ClinVar contains an entry for this variant (Variation ID: 141327). Some submitters cite overlapping but not identical evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018961.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551880.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Glu1335Ala variant was identified in 3 of 680 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome, astrocytoma, and breast or … (more)
The MSH6 p.Glu1335Ala variant was identified in 3 of 680 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome, astrocytoma, and breast or ovarian cancer and was not identified in 694 control chromosomes from healthy individuals (Perez-Cabornero 2013, Rodriguez-Hernandez 2013, Cock-Rada 2018). The variant was also identified in dbSNP (ID: rs564434147 as "With Uncertain significance allele"), ClinVar (6x as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, Color Genomics, and EGL Genetic), and UMD-LSDB (1x as unclassified variant). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 18 of 237668 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 7 of 32242 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 108812 chromosomes (freq: 0.00008), and South Asian in 9 of 28764 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1335 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. | Nikitin AG | Frontiers in oncology | 2020 | PMID: 32547938 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Integrated analysis of mismatch repair system in malignant astrocytomas. | Rodríguez-Hernández I | PloS one | 2013 | PMID: 24073290 |
Evaluating the effect of unclassified variants identified in MMR genes using phenotypic features, bioinformatics prediction, and RNA assays. | Pérez-Cabornero L | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23523604 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH6 | - | - | - | - |
Text-mined citations for rs564434147 ...
HelpRecord last updated Sep 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.