17-43115771-A-G

Position:

• chr17-43115771-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.89T>C​(p.Leu30Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.89T>C	p.Leu30Ser	missense_variant	3/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.89T>C	p.Leu30Ser	missense_variant	3/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Other:1

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T;.;.;.;T;.;T;T;.;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D;T;D;T;D;D;T;D;T;T;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.1	L;L;L;L;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.71	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.3	N;N;N;N;N;N;N;.;N;N;N;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.071	T;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.75
MutPred		0.56		Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);
MVP		0.98
MPC		0.51
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.51
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397509331; hg19: chr17-41267788;