chr3-37033177-A-G

Variant names:

• chr3-37033177-A-G
• rs3774332
• NM_000249.4:c.1558+4245A>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.1558+4245A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 152,232 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.055 (276 hom., cov: 32)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.701
• Publications: 12 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=-0.81).
• BP6: Variant 3-37033177-A-G is Benign according to our data. Variant chr3-37033177-A-G is described in ClinVar as Benign. ClinVar VariationId is 89776.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0718 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.1558+4245A>G		intron	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.1558+4245A>G		intron	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.1459+4245A>G		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.1558+4245A>G		intron	N/A	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1558+4245A>G		intron	N/A	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1558+4245A>G		intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8397 AN: 152114 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.0632

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

GnomAD4 genome AF: 0.0552 AC: 8396 AN: 152232 Hom.: 276 Cov.: 32 AF XY: 0.0552 AC XY: 4107 AN XY: 74432

African (AFR) AF: 0.0259 AC: 1078 AN: 41546

American (AMR) AF: 0.0566 AC: 866 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3470

East Asian (EAS) AF: 0.0306 AC: 159 AN: 5188

South Asian (SAS) AF: 0.0454 AC: 219 AN: 4824

European-Finnish (FIN) AF: 0.0478 AC: 507 AN: 10598

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0735 AC: 4995 AN: 68002

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0699 Hom.: 857

Bravo AF: 0.0546

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.62
PhyloP100		-0.70
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: rs3774332; hg19: chr3-37074668;