chr17-43124017-C-A

Variant names:

• chr17-43124017-C-A
• rs1064793052
• NM_007294.4:c.80G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.80G>T​(p.Cys27Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.52
• Publications: 9 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 74 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 chr17-43124017-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418064.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43124017-C-A is Pathogenic according to our data. Variant chr17-43124017-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 481469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.80G>T	p.Cys27Phe	missense splice_region	Exon 2 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457536 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725430

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108174

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.94		Loss of catalytic residue at L28 (P = 0.0662)
MVP		1.0
MPC		0.53
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 0

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

Other links and lift over

dbSNP: rs1064793052; hg19: chr17-41276034;