17-43067608-C-G

Variant names:

• chr17-43067608-C-G
• rs80187739
• NM_007294.4:c.5074G>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5074G>C​(p.Asp1692His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,454,204 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV004817597: Functional studies also have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation and haploid cell proliferation assays (PMID:20516115, 30209399, 32546644)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1692G) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 4.72
• Publications: 66 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004817597: Functional studies also have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation and haploid cell proliferation assays (PMID: 20516115, 30209399, 32546644).; SCV000076781: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Studies have shown that this missense change results in two alternately spliced products, one with skipping of exon 16 and another with retention of 153 nucleotides of intron 16, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20516115, 21769658, 22505045, 23239986, 25724305, 30209399; internal data).; SCV000699198: Functional studies have demonstrated in vitro splicing aberrations caused by the variant, including exon 17 skipping (Wappenschmidt\_PLos One\_2012; Ahlborn\_BCRT\_2015) and retention of 153bp of intron 17 that is predicted to result in a truncated protein (Ahlborn\_BCRT\_2015; Wappenschmidt\_PLos One\_2012; Thomassen\_BRCA1&2\_BCRT\_2011). One study also showed a significant or total reduction of WT transcript via RT-PCR and agarose gel band sequence analysis (Thomassent\_BRCA1&2\_BCRT\_2011). The variant lies within the BRCT domain and a functional study showed that a cell line with the variant had a 31% reduction in DNA repair (Coupier\_Oncogene\_2004).; SCV000966915: Multiple functional studies using patient RNA provide some evidence that the p.Asp1692His variant causes aberrant splicing (Houdayer 2012 PMID: 22505045, Thomassen 2012 PMID: 21769658, Wappenschmidt 2012 PMID: 23239986, Ahlborn 2015 PMID: 25724305, Woods 2016 PMID: 28781887).; SCV000277819: This variant has also been shown by functional splicing assays to result in abnormal protein transcripts by either skipping of coding exon 15 or in-frame retention of a portion of intron 15 (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Ahlborn LB et al. Breast Cancer Res. Treat., 2015 Apr;150:289-98). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature 2018 Oct;562(7726):217-222).; SCV001346671: Functional studies also have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation and haploid cell proliferation assays (PMID: 20516115, 30209399, 32546644).; SCV000322068: Published functional studies demonstrate a damaging effect: impaired transcriptional activity and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (PMID: 20516115, 28781887, 30209399, 30765603, 33087888); SCV000693542: Experimental studies have shown that this missense change disrupts normal splicing and leads to two alternately spliced products; one lucking exon 16 and another with retention of 153 base pairs of intron 16. This is expected to result in an absent or disrupted protein product and compromised transcription activation activity (PMID: 21769658, 22505045, 25724305).; SCV001133606: Functional studies have shown that this variant is damaging to protein function and aberrant splicing can result in exon 17 skipping (PMIDs: 25724305 (2015) and 30209399 (2018)).; SCV000591568: Assays evaluating peptide binding and structural stability (Lee 2010), or DNA repair (Coupier 2004) yielded intermediate or inconclusive results as compared to wild-type protein function.
• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 72 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 chr17-43063950-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 864924.
• 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 17-43067608-C-G is Pathogenic according to our data. Variant chr17-43067608-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37633.Status of the report is reviewed_by_expert_panel, 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5074G>C	p.Asp1692His	missense splice_region	Exon 16 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5140G>C	p.Asp1714His	missense splice_region	Exon 17 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5140G>C	p.Asp1714His	missense splice_region	Exon 17 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5074G>C	p.Asp1692His	missense splice_region	Exon 16 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5137G>C	p.Asp1713His	missense splice_region	Exon 17 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5074G>C	p.Asp1692His	missense splice_region	Exon 16 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251348 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454204 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723848

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105076

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (8)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Malignant tumor of breast (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.82
MVP		0.93
MPC		0.25
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.74
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
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: rs80187739; hg19: chr17-41219625;