rs56039126

chr17-43093666-G-Achr17-43093666-G-Cchr17-43093666-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.1865C>T(p.Ala622Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A622G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:15
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2520123).
• BP6: Variant 17-43093666-G-A is Benign according to our data. Variant chr17-43093666-G-A is described in ClinVar as [Benign]. Clinvar id is 54371.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093666-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1865C>T	p.Ala622Val	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1865C>T	p.Ala622Val	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 251102 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461768 Hom.: 0 Cov.: 34 AF XY: 0.0000839 AC XY: 61 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000793 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:4

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000212 -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multple papers describe as VUS; ClinVar: 2 B/LB, 3 VUS -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2019	Variant summary: BRCA1 c.1865C>T (p.Ala622Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276900 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.1865C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, however, with limited information (ie, lack of co-occurrence and/or cosegregation data)(Tikhomirova_2007, Wagner_1998, Moghadasi_2013, Anczukow_2008, Borg_2010, Judkins_2005, Lee_2008, Palma_2008, Wong-Brown_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other likely pathogenic/pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908Argfs; BRCA2 c.658_659delGT, p.Val220Ilefs; BRCA2 c.6275_6276delTT, p.Leu2092Profs; BRIP1 c.440dupA, p.Tyr147X), providing supporting evidence for a benign role. Variant was functionally assessed to have no impact on splicing (Anczukow_2008). Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as likely benign/benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	This variant is associated with the following publications: (PMID: 25637381, 18703817, 18284688, 21520273, 17990525, 23231788, 18273839, 23893897, 26898890, 9663595, 21990134, 17924331, 25682074, 20104584, 16267036, 15385441, 19370767, 33087888) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Ala622Val variant was identified in 5 of 26494 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 2 of 38,284 control chromosomes (frequency: 0.00005) from healthy individuals (Wong-Brown 2015, Moghadasi 2013, Momozawa 2018, Borg 2010, Lee 2008, Tikhomirova 2007). The variant was identified in dbSNP (rs56039126) as “with other allele”, ClinVar (classified as benign by Invitae, Color, Integrated Genetics, Ambry Genetics and ENIGMA, uncertain significance by Partners Healthcare, BIC and 2 other submitters and likely benign by GeneDx and University of Michigan), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 14x). The variant was identified in control databases in 15 of 267,978 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 117,956 chromosomes (freq: 0.0001), East Asian in 1 of 19,248 chromosomes (freq: 0.00005), Latino in 1 of 35,080 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish, Finnish, Other and South Asian populations. A clinical laboratory reported that the variant was identified with multiple co-occurring pathogenic variants (BRCA2 c.5722_5723delCT; p.Leu1908Argfs, BRCA2 c.658_659delGT; p.Val220Ilefs, BRCA2 c.6275_6276delTT; p.Leu2092Profs, BRIP1 c.440dupA; p.Tyr147*). In addition, the variant had no demonstrated effect on in vitro splicing (Anczukow 2008). The p.Ala622Val residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	BRCA1: BP1 -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 11, 2015

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Uncertain	0.56	D;.;.;.;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.0	M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D;D;D;D;.;D;D
REVEL	Uncertain	0.56
Sift	Benign	0.057	T;T;T;T;.;T;D
Sift4G	Uncertain	0.037	D;D;D;T;.;D;.
Polyphen		0.63	P;.;.;P;.;.;.
Vest4		0.44
MVP		0.79
MPC		0.19
ClinPred		0.24	T
GERP RS		1.5
Varity_R		0.063
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs56039126; hg19: chr17-41245683; COSMIC: COSV58788174; COSMIC: COSV58788174;