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NM_000249.4(MLH1):c.991G>A (p.Glu331Lys) AND not specified

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Aug 15, 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:
RCV001818518.6

Allele description [Variation Report for NM_000249.4(MLH1):c.991G>A (p.Glu331Lys)]

NM_000249.4(MLH1):c.991G>A (p.Glu331Lys)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.991G>A (p.Glu331Lys)
HGVS:
  • NC_000003.12:g.37020416G>A
  • NG_007109.2:g.32067G>A
  • NM_000249.4:c.991G>AMANE SELECT
  • NM_001167617.3:c.697G>A
  • NM_001167618.3:c.268G>A
  • NM_001167619.3:c.268G>A
  • NM_001258271.2:c.991G>A
  • NM_001258273.2:c.268G>A
  • NM_001258274.3:c.268G>A
  • NM_001354615.2:c.268G>A
  • NM_001354616.2:c.268G>A
  • NM_001354617.2:c.268G>A
  • NM_001354618.2:c.268G>A
  • NM_001354619.2:c.268G>A
  • NM_001354620.2:c.697G>A
  • NM_001354621.2:c.-33G>A
  • NM_001354622.2:c.-33G>A
  • NM_001354623.2:c.-33G>A
  • NM_001354624.2:c.-36-5221G>A
  • NM_001354625.2:c.-36-5221G>A
  • NM_001354626.2:c.-36-5221G>A
  • NM_001354627.2:c.-36-5221G>A
  • NM_001354628.2:c.991G>A
  • NM_001354629.2:c.892G>A
  • NM_001354630.2:c.991G>A
  • NP_000240.1:p.Glu331Lys
  • NP_000240.1:p.Glu331Lys
  • NP_001161089.1:p.Glu233Lys
  • NP_001161090.1:p.Glu90Lys
  • NP_001161091.1:p.Glu90Lys
  • NP_001245200.1:p.Glu331Lys
  • NP_001245202.1:p.Glu90Lys
  • NP_001245203.1:p.Glu90Lys
  • NP_001341544.1:p.Glu90Lys
  • NP_001341545.1:p.Glu90Lys
  • NP_001341546.1:p.Glu90Lys
  • NP_001341547.1:p.Glu90Lys
  • NP_001341548.1:p.Glu90Lys
  • NP_001341549.1:p.Glu233Lys
  • NP_001341557.1:p.Glu331Lys
  • NP_001341558.1:p.Glu298Lys
  • NP_001341559.1:p.Glu331Lys
  • LRG_216t1:c.991G>A
  • LRG_216:g.32067G>A
  • LRG_216p1:p.Glu331Lys
  • NC_000003.11:g.37061907G>A
  • NM_000249.3:c.991G>A
Protein change:
E233K
Links:
dbSNP: rs550914672
NCBI 1000 Genomes Browser:
rs550914672
Molecular consequence:
  • NM_001354621.2:c.-33G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-33G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-33G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-36-5221G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-36-5221G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-36-5221G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-36-5221G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.697G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002066753Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Dec 31, 2020)
germlineclinical testing

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

SCV002570540Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Jul 11, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004024904Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Aug 15, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]
PMID:
26580448
PMCID:
PMC4734119

Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel.

Kwong A, Shin VY, Chen J, Cheuk IWY, Ho CYS, Au CH, Chan KKL, Ngan HYS, Chan TL, Ford JM, Ma ESK.

J Mol Diagn. 2020 Apr;22(4):544-554. doi: 10.1016/j.jmoldx.2020.01.013. Epub 2020 Feb 15.

PubMed [citation]
PMID:
32068069
See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002066753.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.991G>A, in exon 11 that results in an amino acid change, p.Glu331Lys. This sequence change does not appear to have been previously described in individuals with MLH1-related disorders and has been described in the gnomAD database in six individuals with an overall population frequency of 0.0021% (dbSNP rs550914672). The p.Glu331Lys change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. The p.Glu331Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu331Lys change remains unknown at this time.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570540.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: MLH1 c.991G>A (p.Glu331Lys) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.991G>A has been reported in the literature in individuals diagnosed with breast cancer and medulloblastoma without evidence for causality (example: Zhang_2015 and Kwong_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004024904.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024