17-43115777-A-T

Variant names:

• chr17-43115777-A-T
• rs80357266
• NM_007294.4:c.83T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007294.4(BRCA1):​c.83T>A​(p.Leu28Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L28R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 68 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.83T>A	p.Leu28Gln	missense_variant, splice_region_variant	Exon 3 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.83T>A	p.Leu28Gln	missense_variant, splice_region_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;T;.;.;.;T;.;T;T;.;T;D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;T;D;T;T;D;T;T;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.9	L;L;L;L;L;.;.;.;.;.;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.32	N;N;N;N;N;D;N;.;N;N;N;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;.;D;.;D;.;.
Vest4		0.83
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.63
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: -2

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

Other links and lift over

dbSNP: rs80357266; hg19: chr17-41267794;