17-43104193-T-C

Position:

• chr17-43104193-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_001407959.1(BRCA1):​c.-12A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_001407959.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 1.12

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30146003).
• BP6: Variant 17-43104193-T-C is Benign according to our data. Variant chr17-43104193-T-C is described in ClinVar as [Benign]. Clinvar id is 54971.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104193-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.370A>G	p.Ile124Val	missense_variant	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.370A>G	p.Ile124Val	missense_variant	6/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461584 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:1

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000139 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 17, 2010	- -

BRCA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

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). -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.49	T;D;D;T;D;T;D;T;T;D;D;.;D;D;D;T;D
Sift4G	Benign	0.94	T;T;T;T;T;T;.;.;T;.;D;.;D;.;D;.;.
Polyphen		0.90, 0.75, 0.061	.;P;.;.;.;P;.;.;.;.;B;.;.;.;.;.;.
Vest4		0.36
MutPred		0.33		Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);.;Gain of catalytic residue at I124 (P = 0.0067);.;Gain of catalytic residue at I124 (P = 0.0067);.;.;Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);.;Gain of catalytic residue at I124 (P = 0.0067);Gain of catalytic residue at I124 (P = 0.0067);.;
MVP		0.84
MPC		0.13
ClinPred		0.48	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.052
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357448; hg19: chr17-41256210;