rs80357382

Positions:

• chr17-43106457-T-A
• chr17-43106457-T-C
• chr17-43106457-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_007294.4(BRCA1):​c.211A>T​(p.Arg71Trp) 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.16

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43106457-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17693.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43106457-T-A is Pathogenic according to our data. Variant chr17-43106457-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 867340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.211A>T	p.Arg71Trp	missense_variant, splice_region_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.211A>T	p.Arg71Trp	missense_variant, splice_region_variant	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2019

The c.211A>T variant (also known as p.R71W), located in coding exon 3 of the BRCA1 gene, results from an A to T substitution at nucleotide position 211. The arginine at codon 71 is replaced by tryptophan, an amino acid with dissimilar properties. One functional study found that c.211A>T is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A similar alteration affecting this same nucleotide, c.211A>G, has been reported in numerous breast and ovarian cancer patients and families (Villarreal-Garza C et al. Breast Cancer Res. Treat. 2015 Apr;150:389-94; Janavièius R. EPMA J. 2010 Sep;1:397-412; Diez O et al. Int. J. Cancer. 1999 Nov;83:465-9; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18(1):112; Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165(3):687-697; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4) and was observed to result in aberrant splicing, including exon 5 skipping, due to the use of a cryptic splice donor site (Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). Using the BDGP and ESEfinder splice site prediction tools, c.211A>T is predicted to have the same impact on splicing as c.211A>G and is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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	0.81
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;N;N;D;N;D;D;N;N;.;N;N;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.80
MutPred		0.62		Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;
MVP		0.97
MPC		0.41
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.68
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357382; hg19: chr17-41258474;