3-36993455-G-A

Variant names:

• chr3-36993455-G-A
• rs1800734
• ENST00000413740.2:c.-93G>A

Variant summary

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

The ENST00000413740.2(MLH1):​c.-93G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,283,016 control chromosomes in the GnomAD database, including 42,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4663 hom., cov: 33)
  • Exomes 𝑓: 0.25 (38212 hom.)
• Consequence: MLH1 ENST00000413740.2 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -0.737
• Publications: 214 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=-0.75).
• BP6: Variant 3-36993455-G-A is Benign according to our data. Variant chr3-36993455-G-A is described in ClinVar as Benign. ClinVar VariationId is 89600.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000413740.2. 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.-93G>A		upstream_gene	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.-93G>A		upstream_gene	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.-93G>A		upstream_gene	N/A	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000413740.2	TSL:1	c.-93G>A		5_prime_UTR	Exon 1 of 15	ENSP00000416476.2
	MLH1	ENST00000673673.2		c.-93G>A		5_prime_UTR	Exon 1 of 18	ENSP00000500979.2
	MLH1	ENST00000536378.5	TSL:2	c.-725G>A		5_prime_UTR	Exon 1 of 18	ENSP00000444286.2

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35278 AN: 152130 Hom.: 4667 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.246 AC: 278381 AN: 1130768 Hom.: 38212 Cov.: 16 AF XY: 0.251 AC XY: 144931 AN XY: 577786

African (AFR) AF: 0.168 AC: 4557 AN: 27162

American (AMR) AF: 0.329 AC: 14481 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 7963 AN: 24094

East Asian (EAS) AF: 0.545 AC: 20828 AN: 38216

South Asian (SAS) AF: 0.374 AC: 29756 AN: 79520

European-Finnish (FIN) AF: 0.253 AC: 13376 AN: 52930

Middle Eastern (MID) AF: 0.349 AC: 1724 AN: 4946

European-Non Finnish (NFE) AF: 0.213 AC: 172531 AN: 810386

Other (OTH) AF: 0.266 AC: 13165 AN: 49484

GnomAD4 genome AF: 0.232 AC: 35286 AN: 152248 Hom.: 4663 Cov.: 33 AF XY: 0.238 AC XY: 17732 AN XY: 74448

African (AFR) AF: 0.172 AC: 7146 AN: 41542

American (AMR) AF: 0.274 AC: 4192 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1140 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2871 AN: 5178

South Asian (SAS) AF: 0.383 AC: 1850 AN: 4828

European-Finnish (FIN) AF: 0.247 AC: 2620 AN: 10596

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14649 AN: 68016

Other (OTH) AF: 0.262 AC: 552 AN: 2110

Alfa AF: 0.231 Hom.: 18700

Bravo AF: 0.234

Asia WGS AF: 0.445 AC: 1546 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	Colorectal cancer, hereditary nonpolyposis, type 2 (2)
-	-	2	Lynch syndrome (2)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.6
DANN	Benign	0.77
PhyloP100		-0.74
PromoterAI		0.016	Neutral
Mutation Taster		=300/0	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: rs1800734; hg19: chr3-37034946; COSMIC: COSV99212309;