NM_000249.4(MLH1):c.1865T>C (p.Leu622Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 21, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002408581.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1865T>C (p.Leu622Pro)]

NM_000249.4(MLH1):c.1865T>C (p.Leu622Pro)

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.1865T>C (p.Leu622Pro)

HGVS:

NC_000003.12:g.37047652T>C
NG_007109.2:g.59303T>C
NM_000249.4:c.1865T>CMANE SELECT
NM_001167617.3:c.1571T>C
NM_001167618.3:c.1142T>C
NM_001167619.3:c.1142T>C
NM_001258271.2:c.1865T>C
NM_001258273.2:c.1142T>C
NM_001258274.3:c.1142T>C
NM_001354615.2:c.1142T>C
NM_001354616.2:c.1142T>C
NM_001354617.2:c.1142T>C
NM_001354618.2:c.1142T>C
NM_001354619.2:c.1142T>C
NM_001354620.2:c.1571T>C
NM_001354621.2:c.842T>C
NM_001354622.2:c.842T>C
NM_001354623.2:c.842T>C
NM_001354624.2:c.791T>C
NM_001354625.2:c.791T>C
NM_001354626.2:c.791T>C
NM_001354627.2:c.791T>C
NM_001354628.2:c.1865T>C
NM_001354629.2:c.1766T>C
NM_001354630.2:c.1732-865T>C
NP_000240.1:p.Leu622Pro
NP_000240.1:p.Leu622Pro
NP_001161089.1:p.Leu524Pro
NP_001161090.1:p.Leu381Pro
NP_001161091.1:p.Leu381Pro
NP_001245200.1:p.Leu622Pro
NP_001245202.1:p.Leu381Pro
NP_001245203.1:p.Leu381Pro
NP_001341544.1:p.Leu381Pro
NP_001341545.1:p.Leu381Pro
NP_001341546.1:p.Leu381Pro
NP_001341547.1:p.Leu381Pro
NP_001341548.1:p.Leu381Pro
NP_001341549.1:p.Leu524Pro
NP_001341550.1:p.Leu281Pro
NP_001341551.1:p.Leu281Pro
NP_001341552.1:p.Leu281Pro
NP_001341553.1:p.Leu264Pro
NP_001341554.1:p.Leu264Pro
NP_001341555.1:p.Leu264Pro
NP_001341556.1:p.Leu264Pro
NP_001341557.1:p.Leu622Pro
NP_001341558.1:p.Leu589Pro
LRG_216t1:c.1865T>C
LRG_216:g.59303T>C
LRG_216p1:p.Leu622Pro
NC_000003.11:g.37089143T>C
NM_000249.3:c.1865T>C

Protein change:

L264P

Links:

dbSNP: rs63750693

NCBI 1000 Genomes Browser:

rs63750693

Molecular consequence:

NM_001354630.2:c.1732-865T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1865T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1571T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1865T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1571T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.842T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.842T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.842T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.791T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1865T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1766T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002723391	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 21, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17498565, 21404117, 22290698 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002723391

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 21, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

A new interphase fluorescence in situ hybridization approach for genomic rearrangements involving MLH1 and MSH6 in hereditary nonpolyposis colorectal cancer-suspected mutation-negative patients.

Koehler U, Grabowski M, Bacher U, Holinski-Feder E.

Cancer Genet Cytogenet. 2007 May;175(1):81-4. No abstract available.

PubMed [citation]

PMID:: 17498565

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002723391.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.L622P variant (also known as c.1865T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1865. The leucine at codon 622 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a patient with breast and colorectal cancer who met Bethesda criteria for Lynch syndrome and whose colorectal tumor showed loss of MLH1 and PMS2 proteins on immunohistochemical (IHC) analysis (Koehler U et al. Cancer Genet. Cytogenet., 2007 May;175:81-4). This alteration was also reported in an individual diagnosed with colon cancer at 43 who met Amsterdam II criteria for Lynch syndrome. This individual's colon tumor displayed high microsatellite instability (MSI-H) with loss of both MLH1/PMS2 on IHC analysis and co-occurrence with another MLH1 missense alteration was identified, p.A623S, but the phase (whether in cis or trans) was not reported (Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84). This alteration was also identified as somatic in a MSI-H colon tumor that displayed loss of MLH1 and PMS2 on IHC analysis (Ambry internal data). Based on an internal structural assessment, this alteration leads to destabilization of the C-terminal domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60) and pathogenic by the PON-MMR prediction tool (Ali H et al. Hum. Mutat., 2012 Apr;33:642-50). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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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