7-140924603-GCGGCGCCGGCGC-GCGGCGC

Variant names:

• chr7-140924603-GCGGCGC-G
• rs397507458
• NM_001374258.1:c.95_100delGCGCCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004333.6(BRAF):​c.95_100delGCGCCG​(p.Gly32_Ala33del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,528,960 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (3 hom., cov: 31)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: BRAF NM_004333.6 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.0890

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 7-140924603-GCGGCGC-G is Benign according to our data. Variant chr7-140924603-GCGGCGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=2}. Variant chr7-140924603-GCGGCGC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000211 (32/151614) while in subpopulation AFR AF= 0.000459 (19/41426). AF 95% confidence interval is 0.0003. There are 3 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.95_100delGCGCCG	p.Gly32_Ala33del	disruptive_inframe_deletion	Exon 1 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.95_100delGCGCCG	p.Gly32_Ala33del	disruptive_inframe_deletion	Exon 1 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.95_100delGCGCCG	p.Gly32_Ala33del	disruptive_inframe_deletion	Exon 1 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.95_100delGCGCCG	p.Gly32_Ala33del	disruptive_inframe_deletion	Exon 1 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151504 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000397

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000230 AC: 29 AN: 126314 Hom.: 0 AF XY: 0.000245 AC XY: 17 AN XY: 69262

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000196

Gnomad SAS exome AF: 0.000180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000642

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.0000929 AC: 128 AN: 1377346 Hom.: 1 AF XY: 0.0000957 AC XY: 65 AN XY: 679556

Gnomad4 AFR exome AF: 0.000643

Gnomad4 AMR exome AF: 0.000708

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000845

Gnomad4 SAS exome AF: 0.0000886

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000557

Gnomad4 OTH exome AF: 0.000226

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151614 Hom.: 3 Cov.: 31 AF XY: 0.000283 AC XY: 21 AN XY: 74104

Gnomad4 AFR AF: 0.000459

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000398

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.000947

Bravo AF: 0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 08, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25801821, 30826992, 32740981) -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRAF: PM4:Supporting, BS1 -

not specified Benign:2

Feb 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.95_100delGCGCCG (p.Gly32_Ala33del) results in an in-frame deletion that is predicted to remove 2 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00023 in 126314 control chromosomes. The observed variant frequency is approximately 92 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome And Related Conditions phenotype (2.5e-06). To our knowledge, no occurrence of c.95_100delGCGCCG in individuals affected with Noonan Syndrome and Related Conditions has been reported, though it has been reported in samples from cancer patients without evidence of causality (e.g. Cheng_2015, Shen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25801821, 30826992). ClinVar contains an entry for this variant (Variation ID: 40338). Based on the evidence outlined above, the variant was classified as likely benign. -

Aug 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly32_Ala33del in exon 1 of BRAF: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, despite high nearby amino acid conservation, >20 species have a deletio n of the glycine (Gly) and alanine (Ala) residues at positions 32 and 33. This d eletion has also been identified in 0.1% (11/14082) of African chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s397515331). -

RASopathy Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.95_100del, results in the deletion of 2 amino acid(s) of the BRAF protein (p.Gly32_Ala33del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507459, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BRAF-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

BRAF-related disorder Benign:1

Feb 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy Benign:1

May 08, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 05, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507458; hg19: chr7-140624403;