rs2241031

Variant names:

• chr3-37048783-C-T
• rs2241031
• NM_000249.4:c.1990-121C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000249.4(MLH1):​c.1990-121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 979,796 control chromosomes in the GnomAD database, including 86,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12934 hom., cov: 32)
  • Exomes 𝑓: 0.41 (73452 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -3.24
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-37048783-C-T is Benign according to our data. Variant chr3-37048783-C-T is described in ClinVar as Benign. ClinVar VariationId is 89983.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1990-121C>T		intron	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.1897-121C>T		intron	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.1891-121C>T		intron	N/A	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1990-121C>T		intron	N/A	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1896+1100C>T		intron	N/A	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1668-1703C>T		intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61231 AN: 151906 Hom.: 12928 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.410 AC: 339731 AN: 827772 Hom.: 73452 Cov.: 11 AF XY: 0.404 AC XY: 174886 AN XY: 432664

African (AFR) AF: 0.373 AC: 7941 AN: 21274

American (AMR) AF: 0.373 AC: 13977 AN: 37458

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 9059 AN: 21778

East Asian (EAS) AF: 0.118 AC: 4237 AN: 35938

South Asian (SAS) AF: 0.258 AC: 18157 AN: 70374

European-Finnish (FIN) AF: 0.369 AC: 18105 AN: 49078

Middle Eastern (MID) AF: 0.371 AC: 1547 AN: 4170

European-Non Finnish (NFE) AF: 0.458 AC: 250965 AN: 548322

Other (OTH) AF: 0.400 AC: 15743 AN: 39380

GnomAD4 genome AF: 0.403 AC: 61252 AN: 152024 Hom.: 12934 Cov.: 32 AF XY: 0.395 AC XY: 29361 AN XY: 74288

African (AFR) AF: 0.376 AC: 15563 AN: 41438

American (AMR) AF: 0.412 AC: 6302 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3470

East Asian (EAS) AF: 0.0782 AC: 406 AN: 5190

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4820

European-Finnish (FIN) AF: 0.366 AC: 3853 AN: 10532

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31162 AN: 67964

Other (OTH) AF: 0.388 AC: 818 AN: 2110

Alfa AF: 0.431 Hom.: 13548

Bravo AF: 0.404

Asia WGS AF: 0.197 AC: 690 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.011
DANN	Benign	0.68
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2241031; hg19: chr3-37090274;