3-37021363-C-T

Variant names:

• chr3-37021363-C-T
• rs3774339
• NM_000249.4:c.1038+900C>T

Variant summary

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

The NM_000249.4(MLH1):​c.1038+900C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,748 control chromosomes in the GnomAD database, including 11,834 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 0.38 (11834 hom., cov: 31)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890
• Publications: 11 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 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.1038+900C>T		intron	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.1038+900C>T		intron	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.939+900C>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.1038+900C>T		intron	N/A	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1038+900C>T		intron	N/A	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1038+900C>T		intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58157 AN: 151630 Hom.: 11827 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.383 AC: 58174 AN: 151748 Hom.: 11834 Cov.: 31 AF XY: 0.376 AC XY: 27878 AN XY: 74134

African (AFR) AF: 0.319 AC: 13175 AN: 41330

American (AMR) AF: 0.401 AC: 6113 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3470

East Asian (EAS) AF: 0.0774 AC: 399 AN: 5156

South Asian (SAS) AF: 0.223 AC: 1072 AN: 4810

European-Finnish (FIN) AF: 0.365 AC: 3827 AN: 10494

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30820 AN: 67926

Other (OTH) AF: 0.369 AC: 777 AN: 2104

Alfa AF: 0.402 Hom.: 2142

Bravo AF: 0.383

Asia WGS AF: 0.189 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.81
PhyloP100		-0.089
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: rs3774339; hg19: chr3-37062854;