3-37042249-A-G

Variant names:

• chr3-37042249-A-G
• rs9876116
• NM_000249.4:c.1668-19A>G

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.1668-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,544,504 control chromosomes in the GnomAD database, including 137,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.41 (13269 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123996 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:21
• Conservation: PhyloP100: -0.274
• Publications: 35 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: ClinGen, Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-37042249-A-G is Benign according to our data. Variant chr3-37042249-A-G is described in ClinVar as Benign. ClinVar VariationId is 36542.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1668-19A>G		intron	N/A	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1668-19A>G		intron	N/A	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.1569-19A>G		intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1668-19A>G		intron	N/A	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.1668-19A>G		intron	N/A	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1667+1955A>G		intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62105 AN: 151894 Hom.: 13263 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.400

GnomAD2 exomes AF: 0.371 AC: 92862 AN: 250418 AF XY: 0.370

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.0588

Gnomad FIN exome AF: 0.356

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.414 AC: 576566 AN: 1392492 Hom.: 123996 Cov.: 25 AF XY: 0.410 AC XY: 285671 AN XY: 696456

African (AFR) AF: 0.408 AC: 13115 AN: 32128

American (AMR) AF: 0.369 AC: 16415 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10603 AN: 25712

East Asian (EAS) AF: 0.113 AC: 4473 AN: 39486

South Asian (SAS) AF: 0.255 AC: 21757 AN: 85176

European-Finnish (FIN) AF: 0.362 AC: 19306 AN: 53268

Middle Eastern (MID) AF: 0.370 AC: 2092 AN: 5648

European-Non Finnish (NFE) AF: 0.444 AC: 465963 AN: 1048368

Other (OTH) AF: 0.393 AC: 22842 AN: 58162

GnomAD4 genome AF: 0.409 AC: 62124 AN: 152012 Hom.: 13269 Cov.: 32 AF XY: 0.401 AC XY: 29760 AN XY: 74288

African (AFR) AF: 0.410 AC: 17018 AN: 41472

American (AMR) AF: 0.413 AC: 6307 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1400 AN: 3468

East Asian (EAS) AF: 0.0778 AC: 403 AN: 5178

South Asian (SAS) AF: 0.237 AC: 1145 AN: 4822

European-Finnish (FIN) AF: 0.358 AC: 3782 AN: 10552

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

European-Non Finnish (NFE) AF: 0.451 AC: 30641 AN: 67948

Other (OTH) AF: 0.395 AC: 835 AN: 2112

Alfa AF: 0.417 Hom.: 5055

Bravo AF: 0.411

Asia WGS AF: 0.197 AC: 690 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	3	not provided (4)
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
-	-	3	Lynch syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.27
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs9876116; hg19: chr3-37083740; COSMIC: COSV99212311; COSMIC: COSV99212311;