chr3-37001050-T-G

Variant names:

• chr3-37001050-T-G
• rs4647220
• NM_000249.4:c.303T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001167617.3(MLH1):​c.12+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,585,538 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: MLH1 NM_001167617.3 splice_donor, intron
• Clinical Significance: Likely benign reviewed by expert panel B:19 O:1
• Conservation: PhyloP100: -0.441
• 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: 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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.8, offset of 5, new splice context is: gagGTaagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 3-37001050-T-G is Benign according to our data. Variant chr3-37001050-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 90140.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000742 (113/152280) while in subpopulation SAS AF = 0.0226 (109/4824). AF 95% confidence interval is 0.0192. There are 4 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167617.3. 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.303T>G	p.Gly101Gly	synonymous	Exon 3 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.303T>G	p.Gly101Gly	synonymous	Exon 3 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354630.2		c.303T>G	p.Gly101Gly	synonymous	Exon 3 of 18	NP_001341559.1	A0A669KAW3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.303T>G	p.Gly101Gly	synonymous	Exon 3 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.303T>G	p.Gly101Gly	synonymous	Exon 3 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.303T>G	p.Gly101Gly	synonymous	Exon 3 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152162 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00249 AC: 627 AN: 251344 AF XY: 0.00306

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00113 AC: 1621 AN: 1433258 Hom.: 25 Cov.: 26 AF XY: 0.00157 AC XY: 1122 AN XY: 714766

African (AFR) AF: 0.0000609 AC: 2 AN: 32840

American (AMR) AF: 0.0000448 AC: 2 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39478

South Asian (SAS) AF: 0.0174 AC: 1491 AN: 85670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5712

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1086028

Other (OTH) AF: 0.00176 AC: 105 AN: 59516

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152280 Hom.: 4 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.00925 AC: 32 AN: 3472

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.72
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.49	N
PhyloP100		-0.44
ClinPred		0.017	T
GERP RS		-6.8
Mutation Taster		=42/58	disease causing

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: rs4647220; hg19: chr3-37042541;