ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp)
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(3); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp)
Variation ID: 89457 Accession: VCV000089457.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806319 (GRCh38) [ NCBI UCSC ] 2: 48033458 (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 Mar 24, 2015 May 1, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.3762A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Glu1254Asp missense NM_001281492.2:c.3372A>T NP_001268421.1:p.Glu1124Asp missense NM_001281493.2:c.2856A>T NP_001268422.1:p.Glu952Asp missense NM_001281494.2:c.2856A>T NP_001268423.1:p.Glu952Asp missense NC_000002.12:g.47806319A>T NC_000002.11:g.48033458A>T NG_007111.1:g.28173A>T NG_008397.1:g.104357T>A LRG_219:g.28173A>T LRG_219t1:c.3762A>T LRG_219p1:p.Glu1254Asp - Protein change
- E1254D, E952D, E1124D
- Other names
- p.E1254D:GAA>GAT
- Canonical SPDI
- NC_000002.12:47806318:A:T
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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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
9068 | 9375 |
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
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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
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 21, 2021 | RCV000160699.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000212689.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 29, 2023 | RCV000408995.4 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000524187.11 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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May 12, 2023 | RCV000587284.10 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003997096.2 | |
MSH6-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 8, 2023 | RCV004537280.1 |
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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Likely benign
(Feb 10, 2020)
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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: SCV000685443.3
First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020 |
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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: SCV004018969.1
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
(Aug 08, 2023)
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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: SCV004121040.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MSH6 c.3762A>T variant is predicted to result in the amino acid substitution p.Glu1254Asp. This variant was reported in an individual with Colorectal cancer, non-polyposis … (more)
The MSH6 c.3762A>T variant is predicted to result in the amino acid substitution p.Glu1254Asp. This variant was reported in an individual with Colorectal cancer, non-polyposis (Jiang et al 2019. PubMed ID: 30521064; Chan GHJ et al 2018. PubMed ID: 30093976). This variant is reported in 0.075% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48033458-A-T), which is more common than expected for a primary cause of disease. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/89457/). Although we suspect this variant may be benign, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(May 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134441.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
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Likely benign
(Jan 02, 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: SCV000695887.3
First in ClinVar: Mar 17, 2018 Last updated: Mar 30, 2024 |
Comment:
Variant summary: MSH6 c.3762A>T (p.Glu1254Asp) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Four of … (more)
Variant summary: MSH6 c.3762A>T (p.Glu1254Asp) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251194 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.3762A>T, has been reported in the literature in individuals affected with various tumor phenotypes, including colorectal cancer (Lin_2017, Young_2018, Chan_2018, Gong_2019, Dorling_2021), but was also found in several controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.2818C>T (p.Gln940X), in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 30093976, 29945567, 31118792, 32068069, 33471991, 31308508, 31966835). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely Benign
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004835132.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Number of individuals with the variant: 13
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Likely benign
(Sep 12, 2018)
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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: SCV000215311.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Nov 21, 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: SCV002528062.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.3762A>T (p.E1254D) variant has been reported in at least two individuals with colorectal cancer, including one individual meeting the Bethesda criteria for Lynch … (more)
The MSH6 c.3762A>T (p.E1254D) variant has been reported in at least two individuals with colorectal cancer, including one individual meeting the Bethesda criteria for Lynch syndrome and one individual who also had lymphoma and paraganglioma (PMID 30521064, 30093976). This variant was observed in 15/19952 chromosomes in the East Asian subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 89457). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 24, 2015)
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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: SCV000487880.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Feb 03, 2021)
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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: SCV000211327.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26333163, 22290698, 30521064, 30093976)
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Likely benign
(Jan 28, 2024)
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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: SCV000166234.12
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
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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: SCV001549237.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Glu1254Asp variant was identified as a somatic variant in a lung enteric adenocarcinoma sample (Lin 2017) and in a patient affected with Lynch … (more)
The MSH6 p.Glu1254Asp variant was identified as a somatic variant in a lung enteric adenocarcinoma sample (Lin 2017) and in a patient affected with Lynch syndrome, classified as a neutral variant by in silico models (Ali 2012). The variant was also identified in dbSNP (ID: rs375459388) as “With other allele”, ClinVar (as uncertain significance by InSiGHT, Invitae, GeneDx, Counsyl, Color Genomics, and Integrated Genetics, and as likely benign by Ambry Genetics), and Insight Colon Cancer Gene Variant Database (as uncertain significance). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 15 of 276930 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6460 chromosomes (freq: 0.0002), European (Non-Finnish) in 1 of 126480 chromosomes (freq: 0.000008), and East Asian in 13 of 18866 chromosomes (freq: 0.0007). The East Asian allele frequency is 3 times greater than the maximal expected frequency of a pathogenic MSH6 allele (0.0002), increasing the likelihood that this may be a low frequency benign variant in the East Asian population. The variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, o South Asian populations. 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. The p.Glu1254 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. 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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Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
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 |
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel. | Kwong A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32068069 |
Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing. | Garg S | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2019 | PMID: 31308508 |
Mutation spectrum of germline cancer susceptibility genes among unselected Chinese colorectal cancer patients. | Gong R | Cancer management and research | 2019 | PMID: 31118792 |
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. | Jiang W | International journal of cancer | 2019 | PMID: 30521064 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Pancreatic cancer as a sentinel for hereditary cancer predisposition. | Young EL | BMC cancer | 2018 | PMID: 29945567 |
Genetic mutations in lung enteric adenocarcinoma identified using next-generation sequencing. | Lin L | International journal of clinical and experimental pathology | 2017 | PMID: 31966835 |
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 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
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Text-mined citations for rs375459388 ...
HelpRecord last updated Jun 30, 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.