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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002066753	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 31, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002570540	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 11, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 32068069 Citation Link,
SCV004024904	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 15, 2023)	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

SCV002066753

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 31, 2020)

germline

clinical testing

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

SCV002570540

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 11, 2022)

germline

clinical testing

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

Citation Link,

SCV004024904

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 15, 2023)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

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

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

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

#	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: Sep 29, 2024

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