NM_000249.4(MLH1):c.622C>T (p.Pro208Ser) AND not specified

Germline classification:: Uncertain significance (2 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:: RCV001260299.10

Allele description [Variation Report for NM_000249.4(MLH1):c.622C>T (p.Pro208Ser)]

NM_000249.4(MLH1):c.622C>T (p.Pro208Ser)

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.622C>T (p.Pro208Ser)

Other names:

p.P208S:CCC>TCC

HGVS:

NC_000003.12:g.37012044C>T
NG_007109.2:g.23695C>T
NM_000249.4:c.622C>TMANE SELECT
NM_001167617.3:c.328C>T
NM_001167618.3:c.-102C>T
NM_001167619.3:c.-102C>T
NM_001258271.2:c.622C>T
NM_001258273.2:c.-102C>T
NM_001258274.3:c.-102C>T
NM_001354615.2:c.-102C>T
NM_001354616.2:c.-102C>T
NM_001354617.2:c.-102C>T
NM_001354618.2:c.-102C>T
NM_001354619.2:c.-102C>T
NM_001354620.2:c.328C>T
NM_001354621.2:c.-195C>T
NM_001354622.2:c.-308C>T
NM_001354623.2:c.-308C>T
NM_001354624.2:c.-205C>T
NM_001354625.2:c.-205C>T
NM_001354626.2:c.-205C>T
NM_001354627.2:c.-205C>T
NM_001354628.2:c.622C>T
NM_001354629.2:c.523C>T
NM_001354630.2:c.622C>T
NP_000240.1:p.Pro208Ser
NP_000240.1:p.Pro208Ser
NP_001161089.1:p.Pro110Ser
NP_001245200.1:p.Pro208Ser
NP_001341549.1:p.Pro110Ser
NP_001341557.1:p.Pro208Ser
NP_001341558.1:p.Pro175Ser
NP_001341559.1:p.Pro208Ser
LRG_216t1:c.622C>T
LRG_216:g.23695C>T
LRG_216p1:p.Pro208Ser
NC_000003.11:g.37053535C>T
NM_000249.3:c.622C>T
p.P208S

Protein change:

P110S

Links:

dbSNP: rs587781509

NCBI 1000 Genomes Browser:

rs587781509

Molecular consequence:

NM_001167618.3:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-195C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-308C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-308C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-205C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-205C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-205C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-205C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.622C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.328C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.622C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.328C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.622C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.523C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.622C>T - 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
SCV001437220	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28157215, 33471991 Citation Link,
SCV004024897	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

SCV001437220

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 24, 2022)

germline

clinical testing

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

Citation Link,

SCV004024897

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia.

Richter-Pechańska P, Kunz JB, Hof J, Zimmermann M, Rausch T, Bandapalli OR, Orlova E, Scapinello G, Sagi JC, Stanulla M, Schrappe M, Cario G, Kirschner-Schwabe R, Eckert C, Benes V, Korbel JO, Muckenthaler MU, Kulozik AE.

Blood Cancer J. 2017 Feb 3;7(2):e523. doi: 10.1038/bcj.2017.3.

PubMed [citation]

PMID:: 28157215
PMCID:: PMC5386337

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437220.2

#	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.622C>T (p.Pro208Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622C>T has been reported in the literature in one individual affected with T-cell acute lymphoblastic leukemia (Richter-Pechaska_2017), and in both breast cancer cases and controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as of 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, SCV004024897.1

#	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: Oct 26, 2024

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