chr3-37020402-T-C

Variant names:

• chr3-37020402-T-C
• rs63751049
• NM_000249.4:c.977T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 5P and 17B. PM1 PM5 PP3 BP4 BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.977T>C​(p.Val326Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,614,136 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V326E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:29 O:1
• Conservation: PhyloP100: 7.64
• Publications: 34 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 -12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 40 uncertain in NM_000249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37020402-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 231925.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.41998726).
• BP6: Variant 3-37020402-T-C is Benign according to our data. Variant chr3-37020402-T-C is described in ClinVar as Benign. ClinVar VariationId is 42496.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000433 (66/152256) while in subpopulation SAS AF = 0.00166 (8/4824). AF 95% confidence interval is 0.000825. There are 2 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.977T>C	p.Val326Ala	missense	Exon 11 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.977T>C	p.Val326Ala	missense	Exon 11 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.878T>C	p.Val293Ala	missense	Exon 10 of 18	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.977T>C	p.Val326Ala	missense	Exon 11 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.977T>C	p.Val326Ala	missense	Exon 11 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.977T>C	p.Val326Ala	missense	Exon 11 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152138 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000469 AC: 118 AN: 251388 AF XY: 0.000611

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000594 AC: 868 AN: 1461880 Hom.: 2 Cov.: 31 AF XY: 0.000671 AC XY: 488 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000606 AC: 674 AN: 1112000

Other (OTH) AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152256 Hom.: 2 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74448

African (AFR) AF: 0.000144 AC: 6 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000532 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.00109

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	6	not provided (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
-	1	2	Lynch syndrome (3)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Colorectal cancer, non-polyposis (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	Muir-Torré syndrome (1)
-	-	1	Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.62	P
Vest4		0.78
MVP		0.98
MPC		0.17
ClinPred		0.15	T
GERP RS		5.8
PromoterAI		0.0070	Neutral
Varity_R		0.71
gMVP		0.58
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs63751049; hg19: chr3-37061893;