3-37025629-T-A

Variant names:

• chr3-37025629-T-A
• rs193922367
• NM_000249.4:c.1039-8T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000249.4(MLH1):​c.1039-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,225,154 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., cov: 25)
  • Exomes 𝑓: 0.0073 (40 hom.)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.003561
• Clinical Significance: Benign reviewed by expert panel U:1 B:25
• Conservation: PhyloP100: -0.155
• Publications: 8 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-37025629-T-A is Benign according to our data. Variant chr3-37025629-T-A is described in ClinVar as Benign. ClinVar VariationId is 36539.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.1039-8T>A		splice_region intron	N/A	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1039-8T>A		splice_region intron	N/A	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.940-8T>A		splice_region 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.1039-8T>A		splice_region intron	N/A	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.1039-8T>A		splice_region intron	N/A	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1039-8T>A		splice_region intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1502 AN: 132280 Hom.: 6 Cov.: 25

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00340

Gnomad AMR AF: 0.00566

Gnomad ASJ AF: 0.00764

Gnomad EAS AF: 0.00407

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00366

Gnomad MID AF: 0.00752

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00898

GnomAD2 exomes AF: 0.0257 AC: 3016 AN: 117468 AF XY: 0.0249

Gnomad AFR exome AF: 0.0868

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00944

Gnomad EAS exome AF: 0.0215

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.00733 AC: 8010 AN: 1092886 Hom.: 40 Cov.: 19 AF XY: 0.00753 AC XY: 4066 AN XY: 540322

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0213 AC: 441 AN: 20688

American (AMR) AF: 0.00691 AC: 120 AN: 17368

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 85 AN: 17496

East Asian (EAS) AF: 0.00513 AC: 149 AN: 29028

South Asian (SAS) AF: 0.00526 AC: 201 AN: 38240

European-Finnish (FIN) AF: 0.0105 AC: 386 AN: 36708

Middle Eastern (MID) AF: 0.00844 AC: 27 AN: 3198

European-Non Finnish (NFE) AF: 0.00707 AC: 6270 AN: 886772

Other (OTH) AF: 0.00763 AC: 331 AN: 43388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0114 AC: 1506 AN: 132268 Hom.: 7 Cov.: 25 AF XY: 0.0104 AC XY: 666 AN XY: 64110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0201 AC: 661 AN: 32840

American (AMR) AF: 0.00565 AC: 77 AN: 13622

Ashkenazi Jewish (ASJ) AF: 0.00764 AC: 25 AN: 3274

East Asian (EAS) AF: 0.00409 AC: 20 AN: 4894

South Asian (SAS) AF: 0.00293 AC: 13 AN: 4436

European-Finnish (FIN) AF: 0.00366 AC: 29 AN: 7932

Middle Eastern (MID) AF: 0.00826 AC: 2 AN: 242

European-Non Finnish (NFE) AF: 0.0106 AC: 660 AN: 62350

Other (OTH) AF: 0.00891 AC: 16 AN: 1796

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0280 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	1	4	Colorectal cancer, hereditary nonpolyposis, type 2 (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Lynch syndrome 1 (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.78
PhyloP100		-0.15
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0036
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.020		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: rs193922367; hg19: chr3-37067120; COSMIC: COSV104573003;