rs4647225

Variant names:

• chr3-37001765-G-A
• rs4647225
• NM_000249.4:c.306+712G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000249.4(MLH1):​c.306+712G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 151,462 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.042 (203 hom., cov: 32)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.306+712G>A		intron_variant	Intron 3 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.306+712G>A		intron_variant	Intron 3 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6402 AN: 151348 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0455

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0424 AC: 6421 AN: 151462 Hom.: 203 Cov.: 32 AF XY: 0.0413 AC XY: 3056 AN XY: 73996

African (AFR) AF: 0.0806 AC: 3330 AN: 41312

American (AMR) AF: 0.0311 AC: 472 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3468

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.00852 AC: 41 AN: 4810

European-Finnish (FIN) AF: 0.0367 AC: 378 AN: 10308

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0293 AC: 1986 AN: 67876

Other (OTH) AF: 0.0450 AC: 95 AN: 2110

Alfa AF: 0.0431 Hom.: 25

Bravo AF: 0.0435

Asia WGS AF: 0.0140 AC: 50 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.9
DANN	Benign	0.80
PhyloP100		0.41
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: rs4647225; hg19: chr3-37043256;