rs80357244

Variant names:

• chr17-43094720-C-A
• rs80357244
• ENST00000497488.2:c.-78G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43094720-C-A
• chr17-43094720-C-G
• chr17-43094720-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP6

The NM_007294.4(BRCA1):c.811G>T (p.Val271Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V271A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 409371); p.V271G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 252383); p.V271L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 55721); p.V271M: Benign (ClinVar VariationId 55720, 3 stars); p.V271= (synonymous): Likely_benign (ClinVar VariationId 1762164, 1 star); p.V271= (synonymous): Likely_benign (ClinVar VariationId 934452, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.213
• Publications: 37 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Fanconi anemia, complementation group S

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

Classification according to ACMG Germline Pathogenicity v2019

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

Our verdict: Uncertain_significance. The variant received 1 points.

• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 moderate.
• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.811G>T	p.Val271Leu	missense	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407966.1		c.-78G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001394895.1	C9IZW4
	BRCA1	NM_001407967.1		c.-78G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001394896.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000497488.2	TSL:1	c.-78G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	ENSP00000418986.2	C9IZW4
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.811G>T	p.Val271Leu	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.811G>T	p.Val271Leu	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Varity_R		0.13
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80357244;

hg19: chr17-41246737;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar