chr17-43124032-A-G

Variant names:

• chr17-43124032-A-G
• rs80357438
• NM_007294.4:c.65T>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.65T>C​(p.Leu22Ser) 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000077094: Experimental studies have shown that this missense change affects BRCA1 function (PMID:21990134, 25823446, 30209399, 30696104)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L22F) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:2
• Conservation: PhyloP100: 4.17
• Publications: 51 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000077094: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21990134, 25823446, 30209399, 30696104).; SCV000916786: This variant is absent in 245708 control chromosomes, and has been reported in numerous affected individuals in the literature. Additionally, functional evidence has shown the variant to result in reduced HDR levels (Starita_2015).; SCV004823704: Functional studies have shown that this variant results in loss of homology-directed recombination activity of BRCA1 protein (PMID: 25823446, 30219179, 30696104) and disrupts BARD1 binding activity (PMID: 30696104). This variant has been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399).; SCV000213164: "One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222)."; SCV000912062: "This variant has been reported to be functionally abnormal in homology-directed DNA repair assays (PMID: 25823446, 30219179, 30696104), a BARD1 binding assay (PMID: 30696104), and a haploid cell proliferation assay (PMID: 30209399)."; SCV000568441: Published functional studies suggest a damaging effect based on E3 ubiquitin ligase ability, HDR activity, colony size, and liquid medium function, while other functional assays demonstrated BARD1 binding, spot formation, and yeast localization comparable to wild-type (PMID: 25823446, 27272900, 30209399, 30219179); SCV004219470: Comprehensive functional studies indicated that this variant is damaging to E3 ubiquitin-ligase activity of the BRCA1 protein (PMID: 25823446 (2015)).
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 76 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-43124032-A-G is Pathogenic according to our data. Variant chr17-43124032-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55656.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.65T>C	p.Leu22Ser	missense	Exon 2 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.65T>C	p.Leu22Ser	missense	Exon 2 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.65T>C	p.Leu22Ser	missense	Exon 2 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.65T>C	p.Leu22Ser	missense	Exon 2 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.65T>C	p.Leu22Ser	missense	Exon 2 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.65T>C	p.Leu22Ser	missense	Exon 2 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	not provided (2)
1	-	-	Infant-type hemispheric glioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.2	N
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.92
MutPred		0.92		Loss of stability (P = 0.0745)
MVP		0.97
MPC		0.53
ClinPred		0.95	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.84
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80357438; hg19: chr17-41276049;