chr3-37012106-C-T

Variant names:

• chr3-37012106-C-T
• rs556224377
• NM_000249.4:c.677+7C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000249.4(MLH1):​c.677+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,438,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005736
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.222
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-37012106-C-T is Benign according to our data. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-T is described in CliVar as Likely_benign. Clinvar id is 491723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.677+7C>T		splice_region_variant, intron_variant	Intron 8 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.677+7C>T		splice_region_variant, intron_variant	Intron 8 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250866 AF XY: 0.00000738

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1438878 Hom.: 0 Cov.: 28 AF XY: 0.00000418 AC XY: 3 AN XY: 717224

African (AFR) AF: 0.0000302 AC: 1 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090642

Other (OTH) AF: 0.0000167 AC: 1 AN: 59748

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2

Jun 04, 2018

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 10, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 03, 2022

Color Diagnostics, LLC DBA Color Health

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	-0.65
CADD	Benign	7.8
DANN	Benign	0.87
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs556224377; hg19: chr3-37053597;