chr3-37020415-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_000249.4(MLH1):c.990C>T(p.Ile330Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I330I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MLH1
NM_000249.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.26

Publications

1 publications found

Variant links:

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 3-37020415-C-T is Benign according to our data. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020415-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 455467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.26 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.990C>T	p.Ile330Ile	synonymous_variant	Exon 11 of 19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.990C>T	p.Ile330Ile	synonymous_variant	Exon 11 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251344

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 24, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Aug 14, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:1

Nov 21, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Lynch syndrome

Benign:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.33

(source)

DANN

Benign

0.84

PhyloP100

-2.3

PromoterAI

-0.022

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over