chr17-43104953-G-T

Position:

• chr17-43104953-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_007294.4(BRCA1):​c.216C>A​(p.Ser72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2 O:1
• Conservation: PhyloP100: 1.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a turn (size 2) in uniprot entity BRCA1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43104953-G-T is Benign according to our data. Variant chr17-43104953-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.216C>A	p.Ser72Arg	missense_variant	5/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.216C>A	p.Ser72Arg	missense_variant	5/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1 Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 29, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 18, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 16403807, 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 54481). This missense change has been observed in individual(s) with breast cancer (PMID: 28993434). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 72 of the BRCA1 protein (p.Ser72Arg). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;T;.;.;T;T;.;T;T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;T;D;D;T;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;T;D;D;T;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;D;N;N;.;N;N;N;D;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.018	D;D;D;D;D;D;.;D;D;.;D;.;D;.;.;.
Polyphen		0.97, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.;.;.
Vest4		0.71
MutPred		0.26		Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);.;Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);.;Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);.;Loss of ubiquitination at K70 (P = 0.0331);Loss of ubiquitination at K70 (P = 0.0331);.;.;
MVP		0.92
MPC		0.42
ClinPred		0.96	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356967; hg19: chr17-41256970;