rs4647255

Variant names:

• chr3-37008763-T-C
• rs4647255
• NM_000249.4:c.454-51T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.454-51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,491,372 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.031 (93 hom., cov: 32)
  • Exomes 𝑓: 0.026 (535 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.135
• Publications: 9 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=-0.83).
• BP6: Variant 3-37008763-T-C is Benign according to our data. Variant chr3-37008763-T-C is described in ClinVar as Benign. ClinVar VariationId is 90236.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0311 (4737/152344) while in subpopulation AFR AF = 0.0431 (1791/41568). AF 95% confidence interval is 0.0414. There are 93 homozygotes in GnomAd4. There are 2277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 93 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.454-51T>C		intron	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.454-51T>C		intron	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.355-51T>C		intron	N/A	NP_001341558.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.454-51T>C		intron	N/A	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.454-51T>C		intron	N/A	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.454-51T>C		intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4717 AN: 152226 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0237 AC: 5869 AN: 247824 AF XY: 0.0232

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0257 AC: 34400 AN: 1339028 Hom.: 535 Cov.: 20 AF XY: 0.0254 AC XY: 17085 AN XY: 672862

African (AFR) AF: 0.0411 AC: 1267 AN: 30816

American (AMR) AF: 0.0151 AC: 672 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 454 AN: 25406

East Asian (EAS) AF: 0.0000768 AC: 3 AN: 39068

South Asian (SAS) AF: 0.00965 AC: 807 AN: 83608

European-Finnish (FIN) AF: 0.0374 AC: 1981 AN: 52968

Middle Eastern (MID) AF: 0.0480 AC: 266 AN: 5540

European-Non Finnish (NFE) AF: 0.0275 AC: 27528 AN: 1000820

Other (OTH) AF: 0.0253 AC: 1422 AN: 56252

GnomAD4 genome AF: 0.0311 AC: 4737 AN: 152344 Hom.: 93 Cov.: 32 AF XY: 0.0306 AC XY: 2277 AN XY: 74508

African (AFR) AF: 0.0431 AC: 1791 AN: 41568

American (AMR) AF: 0.0268 AC: 411 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0358 AC: 380 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1933 AN: 68030

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0301 Hom.: 54

Bravo AF: 0.0311

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Colorectal cancer, hereditary nonpolyposis, type 2 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lynch syndrome (1)
-	-	1	Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.38
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4647255; hg19: chr3-37050254; COSMIC: COSV51623525;