rs1555596637

Variant names:

• chr17-43104868-A-C
• rs1555596637
• NM_007294.4:c.301T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43104868-A-C
• chr17-43104868-A-G
• chr17-43104868-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000357654.9(BRCA1):​c.301T>G​(p.Tyr101Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y101N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 missense, splice_region
• Scores: Splicing: ADA: 0.00001975
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 49 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37739906).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357654.9. 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.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 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.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.301T>G	p.Tyr101Asp	missense splice_region	Exon 5 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460618 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111028

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.82
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.19	T
Polyphen		0.039	B
Vest4		0.39
MutPred		0.68		Gain of disorder (P = 0.03)
MVP		0.70
MPC		0.16
ClinPred		0.13	T
GERP RS		1.7
PromoterAI		-0.011	Neutral
Varity_R		0.39
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.020		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: rs1555596637; hg19: chr17-41256885;