3-37012106-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000249.4(MLH1):​c.677+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,086 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006047
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-37012106-C-G is Benign according to our data. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37012106-C-G is described in CliVar as Likely_benign. Clinvar id is 762121.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>G		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>G		splice_region_variant, intron_variant	Intron 8 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438878 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 717224

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1090642

Other (OTH) AF: 0.00 AC: 0 AN: 59748

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 25, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Nov 20, 2024

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

Feb 23, 2024

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	-0.68
CADD	Benign	6.0
DANN	Benign	0.77
PhyloP100		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.0
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;